CN107903303A - A kind of liquid-phase synthesis process of cyclic peptide Alaptide - Google Patents
A kind of liquid-phase synthesis process of cyclic peptide Alaptide Download PDFInfo
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- CN107903303A CN107903303A CN201711160926.7A CN201711160926A CN107903303A CN 107903303 A CN107903303 A CN 107903303A CN 201711160926 A CN201711160926 A CN 201711160926A CN 107903303 A CN107903303 A CN 107903303A
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- alaptide
- cyclic peptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a kind of liquid-phase synthesis process of cyclic peptide Alaptide; this method uses the Boc strategies in liquid phase synthesizing method; by the boc-protected L cycloleucines of N-terminal and N hydroxysuccinimides, N; N ' dicyclohexylcarbodiimides are reacted after obtaining Acibenzolar; the boc-protected ring leucyl methyl lactamine of N-terminal is condensed into the hydrochloride of methyl lactamine; Boc protection groups are removed again, amino and carboxylic acid ester groups is carried out ring-closure reaction in alkaline conditions, you can to obtain cyclic peptide Alaptide.Operating procedure of the present invention is simple, of low cost and product yield is high, overcomes the problems such as existing synthetic method cost of material is high, product yield is low, scale is difficult, environmental pressure is big.
Description
Technical field
The invention belongs to peptide synthesis in liquid phase technical field, and in particular to a kind of liquid phase synthesis of cyclic peptide medicine Alaptide
Method.
Background technology
Alaptide is also known as CPA, is a kind of cyclic peptide of cycloleucine and alanine, as a kind of chemicals, was once used for
Skin disease is treated, has positive therapeutic effect in anti-inflammatory and antimicrobial chemical field.The research of three phase of Present clinical shows,
Alaptide has very big potentiality in terms of the treatment of upper respiratory disease, meanwhile, also there is product to the blood pressure of hypertensive patient
The treatment potentiality of pole.CPA can be used as improving brain function nootropics, its many derivatives have the work for being remarkably reinforced memory
Property, can extend the memory retention time of female mice.
Respiratory Distress Syndrome(RDS) refers to that the inside and outside serious disease of lung causes to increase with the damage of pulmonary capillaries diffusivity, permeability
Based on strong, formed using pulmonary edema, hyaline membrane and atelectasis is main pathological change, with progressive respiratory distress and intractable low
Oxygen mass formed by blood stasis is the Acute respiratory distress syndrome of Clinical symptoms.Belong to the severe stage or type of acute lung injury, clinical test
It has been shown that, cyclic peptide Alaptide have Respiratory Distress Syndrome(RDS) positive therapeutic effect.
Obstructive sleep apnea (OSA) is a kind of very universal disease of hyperpietic.Renin-angiotensin
Element-aldosterone system (RAAS) plays central role in controlling of blood pressure.Angiotensins-antagonism of ions agent Losartan is one
The effective antihypertensive drugs of kind.However, reaction of some patients to this medicine is more even worse than other patients, this is a kind of clinical real
Trample, otherwise incremental dose, otherwise another medicine of increase.Clinical test shows that the injection of cyclic peptide Alaptide, can effectively delay
The state of an illness of OSA patient is solved, meanwhile, after Alaptide is injected, the blood pressure continued smooth of patient reduces, and reaches a preferably inspection
Survey result.
GB2127807A discloses a kind of liquid-phase synthesis process of Alaptide, and this method uses the alanine of Cbz protections
With the methyl esters of L- cycloleucines, with N, N '-dicyclohexylcarbodiimide is condensed the dipeptides that is in line, using palladium/hydrocarbonization, sloughs
Cbz groups, flow back to obtain Alaptide in toluene system.This method synthesis cost is higher, and Alaptide yields are only 39%.
The content of the invention
The technical problems to be solved by the invention be to provide a kind of low cost, in high yield, the liquid phase synthesis of easy scale
The method of cyclic peptide Alaptide.
Technical solution is made of following step used by solving above-mentioned technical problem：
1st, L- cycloleucines (H-Cycloleucine-OH) and di-tert-butyl dicarbonate are carried out aminoterminal protection to react,
Obtain N- tertbutyloxycarbonyl-L- cycloleucines (Boc-Cycloleucine-OH).
2nd, using methanol as solvent, alanine (H-Ala-OH) and thionyl chloride or oxalyl chloride are reacted, generate alanine first
The hydrochloride (H-Ala-OMeHCl) of ester.
3rd, using liquid phase synthesizing method, by Boc-Cycloleucine-OH and N- hydroxysuccinimides (HOSu), N, N '-
Dicyclohexylcarbodiimide (DCC) reaction obtains Acibenzolar, then with H-Ala-OMeHCl in aqueous sodium carbonate or bicarbonate
Condensation reaction is carried out in sodium water solution, obtains N- tertbutyloxycarbonyls-ring leucyl methyl lactamine (Boc-Cycloleucine-
Ala-OMe)。
4th, the Boc protection groups of Boc-Cycloleucine-Ala-OMe are removed, then make amino and carboxylic in alkaline conditions
Perester radical carries out ring-closure reaction, obtains cyclic peptide Alaptide.
In above-mentioned steps 1, the specific method of the aminoterminal protection reaction is：H-Cycloleucine-OH is dissolved in four
In the mixed solution or dichloromethane of hydrogen furans and water and the mixed solution of water, sodium carbonate or potassium carbonate are added, in 5~15 DEG C of bars
Di-tert-butyl dicarbonate is added dropwise under part, drip rear normal-temperature reaction 5~8 it is small when, filter out indissoluble thing, removed under reduced pressure tetrahydrofuran
Or dichloromethane, it is 3~4 with lemon acid for adjusting pH, extraction, salt are washed, dry, remove solvent, obtain Boc-Cycloleucine-
OH；Wherein described H-Cycloleucine-OH and sodium carbonate or potassium carbonate, the molar ratio preferably 1 of di-tert-butyl dicarbonate:1.5
~2.5:1.3~2.0.
The concrete operation method of above-mentioned steps 2 is：H-Ala-OH is dissolved in methanol, dichloro is added dropwise under the conditions of 0~5 DEG C
Sulfoxide or oxalyl chloride, after dripping when reaction 1~2 is small under the conditions of 0~10 DEG C, it is small to be then warmed to room temperature reaction 6~8 naturally
When, it is spin-dried for, obtains H-Ala-OMeHCl, the molar ratio preferably 1 of wherein H-Ala-OH and thionyl chloride or oxalyl chloride:2~3.
In above-mentioned steps 3, the specific method of the condensation reaction is：Using tetrahydrofuran as solvent, by Boc-
Cycloleucine-OH is with N- hydroxysuccinimides (HOSu), N, N '-dicyclohexylcarbodiimide (DCC) at -5~10 DEG C
Under the conditions of reaction 3~8 it is small when, then add H-Ala-OMeHCl and aqueous sodium carbonate or sodium bicarbonate aqueous solution, room temperature
When reaction 6~10 is small, isolates and purifies, obtain Boc-Cycloleucine-Ala-OMe；Wherein described Boc-Cycloleucine-
OH, HOSu, DCC, H-Ala-OMeHCl, the molar ratio preferably 1 of sodium carbonate or sodium acid carbonate:1~1.3:1.1~1.5:1~
2:3~5.
In above-mentioned steps 4, Boc protection groups are removed using HCl- ethyl acetate or HCl-1,4- dioxane system.
In above-mentioned steps 4, the alkaline condition refers to pH=9~11, it preferably passes through sodium carbonate, sodium acid carbonate, N-
Methyl morpholine, N, N '-diisopropylethylamine or 1-methyl-2-pyrrolidinone are adjusted.
Beneficial effects of the present invention are as follows：
1st, the present invention is using Boc strategies, by the hydrochloride of the boc-protected L- cycloleucines of N-terminal and methyl lactamine through contracting
The boc-protected ring leucyl methyl lactamine of N-terminal is synthesized, then removes Boc protection groups, makes amino and carboxylate in alkaline conditions
Base carries out ring-closure reaction, obtains cyclic peptide Alaptide, intermediate needs not move through column chromatography purifying, relative to traditional synthesis side
Method, amino acid dosage is few, avoids the costly use of resin and the use of high poison solvent piperidines, synthesis cost is relatively low, easily
It is small to environmental pressure in scale.
2nd, the present invention protects the N-terminal of H-Cycloleucine-OH using Boc, avoid costly and danger palladium
The use of carbon and high toxicity solvent toluene, protection group is easy to removing, and reaction condition is gentle, easily operated, and Alaptide yields
It can reach more than 73%.
Embodiment
With reference to embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited only to these realities
Apply example.
Embodiment 1
1st, added in 500mL single port bottles 12.9g (0.1mol) H-Cycloleucine-OH, 100mL tetrahydrofuran,
150mL water, stirs to solid and 21.2g (0.2mol) sodium carbonate is added after dissolving, be then slowly added dropwise under the conditions of 5~15 DEG C
35mL (0.15mol) di-tert-butyl dicarbonate, drip rear normal-temperature reaction 6 it is small when, TLC shows that the reaction was complete, filters out indissoluble
Thing, removed under reduced pressure tetrahydrofuran, is extracted with ethyl acetate (100mL × 3 time) after adjusting pH=3 with citric acid, and organic phase is through full
After brine It, anhydrous sodium sulfate drying, removed under reduced pressure solvent, obtains 20g Boc-Cycloleucine-OH.
2nd, 17.8g (0.2mol) H-Ala-OH, 200mL methanol is added in 500mL single port bottles, stirs to solid and dissolves,
29mL (0.4mol) thionyl chloride is added dropwise under the conditions of 0~5 DEG C, after dripping when reaction 2 is small under the conditions of 0~10 DEG C, then
Warm naturally to room temperature reaction 7 it is small when, be spin-dried for solvent, obtain 24g H-Ala-OMeHCl.
3rd, 20g (0.087mol) Boc-Cycloleucine-OH, 500mL tetrahydrofuran, 11g are added in 1L single port bottles
(0.095mol) HOSu, 26.8g (0.130mol) DCC, when reaction 7 is small under the conditions of -5~5 DEG C, TLC shows that the reaction was complete, mistake
Insoluble matter is filtered, 20g (0.143mol) H-Ala-OMeHCl, 30g (0.360mol) sodium acid carbonate, 80mL are added into filtrate
Distilled water, when stirring at normal temperature reaction 8 is small, TLC shows that the reaction was complete, filters out indissoluble impurity, is spin-dried for solvent, adds 200mL and steams
Distilled water and 300mL ethyl acetate, extract organic phase, and organic phase is spin-dried for molten after saturated common salt water washing, anhydrous sodium sulfate drying
Agent, obtains 27g Boc-Cycloleucine-Ala-OMe.
4th, 27g Boc-Cycloleucine-Ala-OMe, 500mL ethyl acetate are added in 1L reaction bulbs, 0~10
HCl gases are continually fed at DEG C, when stirring reaction 4 is small, is spin-dried for obtaining grease, adds 500mL tetrahydrofurans, 40mL N- first
Base morpholine, it is 9~10 to make system pH, when normal-temperature reaction 8 is small, is spin-dried for solvent, adds 200mL ethyl acetate and 200mL
The HCl/water solution of 0.5mol/L, extracts liquid separation, and organic phase depressurizes precipitation after saturated common salt water washing, anhydrous sodium sulfate drying,
Add methyl tertiary butyl ether(MTBE) in -4 DEG C freezing 6 it is small when more than, have solid precipitation, filter, with 300mL methyl tertiary butyl ether(MTBE)s mashing wash
Wash, filter, vacuum drying, obtains 14.2g cyclic peptide Alaptide, yield 78%.
Embodiment 2
1st, added in 500mL single port bottles 19.3g (0.15mol) H-Cycloleucine-OH, 100mL dichloromethane,
200mL water, stirs to solid and 41g (0.3mol) potassium carbonate is added after dissolving, 51mL is slowly added dropwise under the conditions of 5~10 DEG C
(0.22mol) di-tert-butyl dicarbonate, drip rear normal-temperature reaction 6 it is small when, TLC shows that the reaction was complete, filters out indissoluble thing, subtracts
Pressure-off removes dichloromethane, (100mL × 3 time) is extracted with ethyl acetate after adjusting pH=3 with citric acid, organic phase is through saturated common salt
After water washing, anhydrous sodium sulfate drying, removed under reduced pressure solvent, obtains 31g Boc-Cycloleucine-OH.
2nd, 17.8g (0.2mol) H-Ala-OH, 200mL methanol is added in 500mL single port bottles, stirs to solid and dissolves,
34mL (0.4mol) oxalyl chloride is added dropwise under the conditions of 0~5 DEG C, after dripping when reaction 2 is small under the conditions of 0~10 DEG C, then certainly
So be warming up to room temperature reaction 7 it is small when, be spin-dried for solvent, obtain 28g H-Ala-OMeHCl.
3rd, 31g (0.135mol) Boc-Cycloleucine-OH, 500mL tetrahydrofuran, 17g are added in 1L single port bottles
(0.148mol) HOSu, 41.2g (0.2mol) DCC, when reaction 4 is small under the conditions of 0~10 DEG C, TLC shows that the reaction was complete, mistake
Filter, 25g (0.18mol) H-Ala-OMeHCl, 38g (0.45mol) sodium acid carbonate, 100mL distilled water is added into filtrate, often
When temperature stirring reaction 8 is small, TLC show that the reaction was complete, filters out indissoluble impurity, is spin-dried for solvent, add 200mL distilled water with
300mL ethyl acetate, extract organic phase, organic phase successively the aqueous hydrochloric acid solution washing through 0.5mol/L, saturated common salt water washing,
Solvent is removed after anhydrous sodium sulfate drying, obtains 40g Boc-Cycloleucine-Ala-OMe.
4th, 40g Boc-Cycloleucine-Ala-OMe, 500mL1,4- dioxane, 0 are added in 1L reaction bulbs
HCl gases are continually fed under the conditions of~10 DEG C, under the conditions of 0~5 DEG C stirring 5 it is small when after remove solvent, be spin-dried for obtaining grease,
500mL tetrahydrofurans, 50mLN- methyl morpholines are added, it is 9~10 to make system pH, when normal-temperature reaction 8 is small, is spin-dried for solvent, is added
The HCl/water solution of 200mL ethyl acetate and 200mL0.5mol/L, extracts liquid separation, and organic phase depressurizes after being dried over anhydrous sodium sulfate
Precipitation, dissolves enriched product with dichloromethane, column chromatography is carried out (with petroleum ether and ethyl acetate volume with 100~200 mesh silica gel
Than for 3:1 mixed liquor is eluant, eluent), obtain 20g cyclic peptide Alaptide, yield 73%.
Embodiment 3
1st, added in 1000mL single port bottles 50g (0.38mol) H-Cycloleucine-OH, 150mL tetrahydrofuran,
500mL water, stirs to solid and 80g (0.76mol) sodium carbonate is added after dissolving, 130mL is slowly added dropwise under the conditions of 5~15 DEG C
(0.57mol) di-tert-butyl dicarbonate, drip rear normal-temperature reaction 6 it is small when, TLC shows that the reaction was complete, filters out indissoluble thing, subtracts
Pressure-off removes tetrahydrofuran, (200mL × 3 time) is extracted with ethyl acetate after adjusting pH=3 with citric acid, organic phase is through saturated common salt
After water washing, anhydrous sodium sulfate drying, removed under reduced pressure solvent, obtains 80g Boc-Cycloleucine-OH.
2nd, 38.2g (0.43mol) H-Ala-OH, 500mL methanol is added in 1000mL single port bottles, is stirred molten to solid
Solution, is added dropwise 62mL (0.86mol) thionyl chloride under the conditions of 0~5 DEG C, after dripping when reaction 2 is small under the conditions of 0~10 DEG C,
Then warm naturally to room temperature reaction 7 it is small when, be spin-dried for solvent, obtain 60g H-Ala-OMeHCl.
3rd, added in 2L single port bottles 80g (0.350mol) Boc-Cycloleucine-OH, 800mL tetrahydrofuran,
44.2g (0.385mol) HOSu, 108g (0.520mol) DCC, when reaction 8 is small under the conditions of 0~10 DEG C, TLC displays have been reacted
Entirely, indissoluble thing is filtered out, 53.5g (0.383mol) H-Ala-OMeHCl, 117g (1.390mol) carbonic acid is added into filtrate
Hydrogen sodium, 200mL distilled water, when stirring at normal temperature reaction 8 is small, TLC shows that the reaction was complete, filters out indissoluble impurity, is spin-dried for solvent, adds
Enter 400mL distilled water and 400mL ethyl acetate, extract organic phase, water is mutually extracted with ethyl acetate (each 150mL) twice, closes
And organic phase, the aqueous hydrochloric acid solution for adding 300mL0.5mol/L wash organic phase, saturated common salt water washing, anhydrous sodium sulfate is done
It is dry, obtain 108g grease Boc-Cycloleucine-Ala-OMe.
4th, 108g Boc-Cycloleucine-Ala-OMe, 600mL ethyl acetate are added in 1L reaction bulbs, 0~5
Be continually fed into HCl gases under the conditions of DEG C, when stirring 6 is small after remove solvent, be spin-dried for obtaining grease, add 500mL tetrahydrofurans,
80mLN- methyl morpholines, it is 9~10 to make system pH, when normal-temperature reaction 10 is small, is spin-dried for solvent, add 500mL ethyl acetate and
The HCl/water solution washing extraction of 600mL0.5mol/L, organic phase are dried over anhydrous sodium sulfate rear removed under reduced pressure solvent, use dichloro
Methane dissolves enriched product, and column chromatography is carried out (using petroleum ether and ethyl acetate volume ratio as 3 with 100~200 mesh silica gel:1 mixing
Liquid is eluant, eluent), obtain 51g cyclic peptide Alaptide, yield 73.6%.
Claims (10)
1. a kind of liquid-phase synthesis process of cyclic peptide Alaptide, it is characterised in that this method is made of following step：
(1) L- cycloleucines and di-tert-butyl dicarbonate are carried out aminoterminal protection to react, it is bright obtains N- tertbutyloxycarbonyl-L- rings
Propylhomoserin；
(2) using methanol as solvent, alanine and thionyl chloride or oxalyl chloride are reacted, generate the hydrochloride of methyl lactamine；
(3) liquid phase synthesizing method is used, by N- tertbutyloxycarbonyl-L- cycloleucines and N- hydroxysuccinimides, the hexamethylene of N, N '-two
Base carbodiimide reacts to obtain Acibenzolar, then with the hydrochloride of methyl lactamine in aqueous sodium carbonate or sodium bicarbonate aqueous solution
Middle carry out condensation reaction, obtains N- tertbutyloxycarbonyls-ring leucyl methyl lactamine；
(4) the tertbutyloxycarbonyl protection group of N- tertbutyloxycarbonyls-ring leucyl methyl lactamine is removed, then in alkaline conditions
Amino and carboxylic acid ester groups is carried out ring-closure reaction, obtain cyclic peptide Alaptide.
2. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 1, it is characterised in that：In step (1), institute
Stating the specific method that aminoterminal protection is reacted is：L- cycloleucines are dissolved in the mixed solution or dichloromethane of tetrahydrofuran and water
With in the mixed solution of water, adding sodium carbonate or potassium carbonate, di-tert-butyl dicarbonate being added dropwise under the conditions of 5~15 DEG C, drips
When normal-temperature reaction 5~8 is small afterwards, indissoluble thing, removed under reduced pressure tetrahydrofuran or dichloromethane are filtered out, is 3 with lemon acid for adjusting pH
~4, extraction, salt are washed, dry, remove solvent, obtain N- tertbutyloxycarbonyl-L- cycloleucines.
3. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 2, it is characterised in that：In step (1), institute
It is 1 that L- cycloleucines, which are stated, with sodium carbonate or potassium carbonate, the molar ratio of di-tert-butyl dicarbonate:1.5~2.5:1.3~2.0.
4. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 1, it is characterised in that：The step (2)
Concrete operation method is：Alanine is dissolved in methanol, thionyl chloride or oxalyl chloride are added dropwise under the conditions of 0~5 DEG C, after dripping
Under the conditions of 0~10 DEG C reaction 1~2 it is small when, be then warmed to room temperature naturally reaction 6~8 it is small when, be spin-dried for, obtain methyl lactamine
Hydrochloride.
5. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 4, it is characterised in that：In step (2), institute
It is 1 that alanine, which is stated, with the molar ratio of thionyl chloride or oxalyl chloride:2~3.
6. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 1, it is characterised in that：In step (3), institute
The specific method for stating condensation reaction is：Using tetrahydrofuran as solvent, by N- tertbutyloxycarbonyl-L- cycloleucines and N- hydroxyls fourth two
Then acid imide, N, N '-dicyclohexylcarbodiimide add methyl lactamine when reaction 3~8 is small under the conditions of -5~10 DEG C
Hydrochloride and aqueous sodium carbonate or sodium bicarbonate aqueous solution, when normal-temperature reaction 6~10 is small, isolate and purify, and obtain N-terminal protection
Ring leucyl methyl lactamine.
7. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 6, it is characterised in that：In step (3), institute
State N- tertbutyloxycarbonyl-L- cycloleucines, N- hydroxysuccinimides, N, N '-dicyclohexylcarbodiimide, methyl lactamine
The molar ratio of hydrochloride, sodium carbonate or sodium acid carbonate is 1:1~1.3:1.1~1.5:1~2:3~5.
8. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 1, it is characterised in that：In step (4), adopt
With HCl- ethyl acetate or HCl-1,4- dioxane system removing tertbutyloxycarbonyl.
9. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 1, it is characterised in that：In step (4), institute
The alkaline condition stated refers to pH=9~11.
10. the liquid-phase synthesis process of cyclic peptide Alaptide according to claim 9, it is characterised in that：The alkaline bar
Part is adjusted by sodium carbonate, sodium acid carbonate, N-methylmorpholine, N, N '-diisopropylethylamine or 1-methyl-2-pyrrolidinone.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109438363A (en) * | 2018-10-31 | 2019-03-08 | 陕西慧康生物科技有限责任公司 | A kind of liquid phase high-purity scale synthetic method of ring (leucyl-arginyl) dipeptides salt |
| CN111943894A (en) * | 2019-05-17 | 2020-11-17 | 南京爱德程医药科技有限公司 | Synthesis method of 4, 7-diazaspiro [2.5] octane compound |
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| GB2127807A (en) * | 1982-10-01 | 1984-04-18 | Spofa Vereinigte Pharma Werke | 2,5-Piperazinediones |
| CN101480374A (en) * | 2009-01-20 | 2009-07-15 | 苏州中化药品工业有限公司 | Stable solid pharmaceutical composition |
| WO2014019556A1 (en) * | 2012-08-02 | 2014-02-06 | University Of Veterinary And Pharmaceutical Sciences Brno Faculty Of Pharmacy | Alaptide : methods of effecting its solubility, membrane permeation and pharmaceutical compositions for human and/or veterinary applications |
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| GB2127807A (en) * | 1982-10-01 | 1984-04-18 | Spofa Vereinigte Pharma Werke | 2,5-Piperazinediones |
| CN101480374A (en) * | 2009-01-20 | 2009-07-15 | 苏州中化药品工业有限公司 | Stable solid pharmaceutical composition |
| WO2014019556A1 (en) * | 2012-08-02 | 2014-02-06 | University Of Veterinary And Pharmaceutical Sciences Brno Faculty Of Pharmacy | Alaptide : methods of effecting its solubility, membrane permeation and pharmaceutical compositions for human and/or veterinary applications |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109438363A (en) * | 2018-10-31 | 2019-03-08 | 陕西慧康生物科技有限责任公司 | A kind of liquid phase high-purity scale synthetic method of ring (leucyl-arginyl) dipeptides salt |
| CN109438363B (en) * | 2018-10-31 | 2022-04-29 | 陕西慧康生物科技有限责任公司 | Liquid-phase high-purity large-scale synthesis method of cyclic (leucyl-arginyl) dipeptide salt |
| CN111943894A (en) * | 2019-05-17 | 2020-11-17 | 南京爱德程医药科技有限公司 | Synthesis method of 4, 7-diazaspiro [2.5] octane compound |
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