CN107501390A - Tiopronin acyl-Met-AA, it is synthesized, activity and application - Google Patents

Tiopronin acyl-Met-AA, it is synthesized, activity and application Download PDF

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CN107501390A
CN107501390A CN201610422889.1A CN201610422889A CN107501390A CN 107501390 A CN107501390 A CN 107501390A CN 201610422889 A CN201610422889 A CN 201610422889A CN 107501390 A CN107501390 A CN 107501390A
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met
obzl
tiopronin
acyl
residue
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CN107501390B (en
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赵明
彭师奇
王玉记
吴建辉
刘程
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Capital Medical University
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Capital Medical University
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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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

The invention discloses the Tiopronin acyl Met AA of following formula, AA is selected from glycine residue, L valine residues, L leucine residues, L isoleucine residues, L asparagicacid residues, L glutaminic acid residues, L tyrosine residues, L proline residues, L alanine residues, L methionine residues, L phenylalanine residues and L trp residues in formula.Their preparation method is disclosed, discloses their lead discharging activity, thus the invention discloses their applications in lead discharging medicine is prepared.

Description

Tiopronin acyl-Met-AA, it is synthesized, activity and application
Technical field
The present invention relates to Tiopronin acyl-Met-AA, it is related to their preparation method, is related to their lead discharging activity, because And the present invention relates to their applications as lead discharging medicine.The invention belongs to biomedicine field.
Background technology
Lead is widely existed in the routine work life of people, and is a kind of huge sum of money that can be caused a disease for human body Category.Lead can be entered in human body by number of ways, and can be accumulated in human body, so as to cause to damage to human body.Lead enters After entering human body, the binding site with albumen can be competed with metal ion, so as to influence the normal physiological function of human body.In lead Poison has serious influence to people, is the most serious for the influence in budding children.Internal low-level blood lead is dense Degree can have an impact to the development of the nervous system of children, cause its intelligence to decline.Lead can caused by lipid peroxidation, can draw Angiocardiopathy and geriatric disease, its consequence such as the hypertension risen are progressively paid attention to.Thus heavy metal detoxification lead discharging medicine It is the important directions of current drug research.
The drive lead medicine of Present clinical has various limitations：Some medicines are not thorough to brain lead drive row；Some medicines Lead is not excreted timely and causes lead to be redistributed in body；Some need to be injected intravenously, and are brought inconvenience to medication. So finding, a kind of safety, curative effect are high, selectivity is strong and medication easily drives lead medicine and has good application prospect.
Tiopronin is the compound containing sulfydryl, has the function that heavy metal drive row.The effective dose of Tiopronin lead discharging For 490 μm of ol/kg.Obviously, this is higher dosage.By long-felt, it is found by the applicant that it is general to modify sulphur with dipeptides Met-AA Luo Ning, effective dose can be made to reduce by 100 times, and other trace elements in vivo are not influenceed.This is unexpected technology Effect.According to these discoveries and understanding, the invention is inventors herein proposed.
The content of the invention
First content of the present invention is to provide 12 kinds of Tiopronin acyl-Met-AA, and AA is selected from glycine residue, L- in formula Valine residue, L-Leu residue, ILE residue, L-Aspartic acid residue, Pidolidone residue, TYR are residual Base, L-PROLINE residue, ALANINE residue, METHIONINE residue, L-phenylalanine residue and L-Trp residue.
Second content of the present invention is to provide 12 kinds of Tiopronin acyl-Met-AA synthetic method, and this method includes：
(1) dicyclohexylcarbodiimide (DCC), 1- hydroxy benzo triazoles (HOBt) catalysis under press standard method system Standby 12 kinds of Boc-Met-AA-OBzl；
(2) 12 kinds of Boc-Met-AA-OBzl 0 DEG C of de- Boc, change into 12 in the ethyl acetate solution of 4N hydrogen chloride Kind HClMet-AA-OBzl；
(3) dicyclohexylcarbodiimide (DCC), 1- hydroxy benzo triazoles (HOBt) catalysis under prepare 12 kinds of sulphur it is general Luo Ning acyls-Met-AA-OBzl；
(4) 12 kinds of Tiopronin acyl-Met-AA-OBzl change into 12 kinds of Tiopronins under the effect of the 2N NaOH aqueous solution Acyl-Met-AA.
The 3rd content of the present invention is that 12 kinds of Tiopronin acyl-Met-AA oral medication lead dischargings in 7 days of evaluation are active and right The influence of other metallic elements.
The 4th content of the present invention is the representative compound for evaluating various dose to the drive row of brain lead and bone lead activity.
The 5th content of the present invention is that 12 kinds of Tiopronin acyl-Met-AA oral medication lead dischargings in 20 days of evaluation are active and right The influence of other metallic elements.
Brief description of the drawings
Fig. 1 .12 kind Tiopronin acyls-Met-AA synthetic route .i) AA-OBzl, DCC, HOBt, NMM, THF；ii)4N The ethyl acetate solution of hydrogen chloride；iii)2N NaOH,THF；A, AA=Ala；B, AA=Gly；C, AA=Ile；D, AA=Leu； E, AA=Phe；F, AA=Trp；G, AA=Val；H, AA=Tyr；I, AA=Asp；J, AA=Glu；K, AA=Pro；L, AA= Met。
Embodiment
In order to which the present invention is expanded on further, a series of embodiments are given below.These embodiments be entirely it is illustrative, it Only be used for the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares Boc-Met-Ala-OBzl (2a)
4g (16.0mmol) Boc-Met is added in 250mL eggplant bottles with 100mL anhydrous tetrahydro furans (THF) that its is molten Solve, 2.4g (16.8mmol) 1- hydroxy benzo triazoles (HOBt) are added under ice bath (0 DEG C), are completely dissolved.4.4g is slowly added dropwise The THF solution of (20.8mmol) dicyclohexylcarbodiimide (DCC), after reaction solution activates 30min, there are a large amount of dicyclohexylurea (DCU)s (DCU) generate, 4.1g (2.0mmol) HClAla-OBzl is added in reaction solution under condition of ice bath, uses N-methylmorpholine (NMM) pH value is adjusted to 8-9.12h, TLC monitoring reaction process (methylene chloride/methanol=20 are stirred at room temperature:1), raw material point Disappear.It is filtered under diminished pressure and removes DCU, filtrate decompression removes solvent.With 100mL ethyl acetate dissolution residual substances, saturation is used successively NaHCO3The aqueous solution (30mL × 3), saturation NaCl solution (30mL × 3), saturation KHSO4Solution (30mL × 3), saturation NaCl are molten Liquid (30mL × 3), saturation NaHCO3Solution (30mL × 3) and saturation NaCl solution (30mL × 3) washing, ethyl acetate phase nothing Water Na2SO4More than 2h is dried, is filtered to remove Na2SO4, filtrate decompression removing solvent, 7g (80%) title compound is obtained, is yellow Grease.
Embodiment 2 prepares HClMet-Ala-OBzl (3a)
7g (16.0mmol) Boc-Met-Ala-OBzl is added in 250mL eggplant bottles, it is molten with 20mL anhydrous ethyl acetates Solution, the ethyl acetate solution of 70mL 4N hydrogen chloride is added under ice bath (0 DEG C), stirring reaction 2h, TLC monitor reaction under ice bath Process, raw material point disappearance (methylene chloride/methanol=20:1), reaction solution is concentrated under reduced pressure with water pump.By residue with anhydrous second It is concentrated under reduced pressure after acetoacetic ester dissolving, 3 times repeatedly, adds absolute ether infiltration residue, then be concentrated under reduced pressure, 3 times repeatedly, must be marked Compound is inscribed, is yellow oil.
Embodiment 3 prepares Tiopronin acyl-Met-Ala-OBzl (4a)
2.6g (16.0mmol) Tiopronin is added in 250mL eggplant bottles, is dissolved in the anhydrous THF of 100mL, ice bath (0 DEG C) under add 2.4g (16.8mmol) HOBt, 4.4g (20.8mmol) DCC THF solution is slowly added dropwise, reaction solution is activated 30min, there are a large amount of DCU to separate out, add 7.0g (16mmol) HClMet-Ala-OBzl in reaction solution under condition of ice bath, PH value is adjusted to 8-9 with NMM.Reaction 8h, TLC monitoring reaction process (petrol ether/ethyl acetate=1 is stirred at room temperature:4), raw material Point disappears.It is filtered under diminished pressure and removes DCU, filtrate decompression removes solvent.Residue 100mL ethyl acetate dissolves, and uses saturation successively NaHCO3Solution (30mL × 3), saturation NaCl solution (30mL × 3), saturation KHSO4Solution (30mL × 3), saturation NaCl solution (30mL × 3), saturation NaHCO3Solution (30mL × 3) and saturation NaCl solution (30mL × 3) washing, ethyl acetate phase is with anhydrous Na2SO4More than 2h is dried, is filtered to remove Na2SO4, filtrate decompression removing solvent, obtain yellow oil.By this yellow oil Carry out silica gel reduced pressure chromatography and isolate and purify (petrol ether/ethyl acetate=1:2) 0.9g (12.4%) title compound, is obtained, is Colorless solid.ESI-MS(m/e):456[M+H]+；Mp:107-108℃；IR(cm-1): 3273,1729,1544,1451,1370,1336,1317,1168,1138,699；1H-NMR(300MHz,DMSO-d6):δ/ppm =8.47 (m, 1H), 8.22 (m, 1H), 8.02 (m, 1H), 7.36 (m, 5H), 5.11 (s, 2H), 4.36 (m, 1H), 4.30 (m, 1H), 3.72 (m, 2H), 3.55 (m, J=6.0Hz, 1H), 2.88 (s, 1H), 2.42 (m, 2H), 1.99 (s, 3H), 1.87 (m, 1H), 1.76 (m, 1H), 1.33 (d, J=6.0Hz, 3H), 1.32 (m, 3H).
Embodiment 4 prepares Tiopronin acyl-Met-Ala (5a)
300mg (0.62mmol) Tiopronin acyl-Met-Ala-OBzl is added in 100mL eggplant bottles, with 10mL THF Dissolved, 6mL2N NaOH solutions are added under ice bath (0 DEG C) and adjust reacting liquid pH value to 12, continue to stir under condition of ice bath Reaction.TLC monitors reaction process, after raw material point disappears, with saturation KHSO4Solution adjusts reacting liquid pH value to 6-7, is concentrated under reduced pressure THF is removed, is extracted (30mL × 3) with ethyl acetate, aqueous phase saturation KHSO4Solution adjusts pH value to 2, uses ethyl acetate Extracted (50mL × 3), organic phase anhydrous Na2SO4More than 2h is dried, is filtered to remove Na2SO4, filtrate decompression removes molten Agent, 90mg (32%) title compound is worn away to obtain with absolute ether, is colorless solid.ESI-MS(m/e):364[M-H]-；Mp: 120-121℃；IR(cm-1):3299,3065,2922,1738,1450,1337,1315, 1284,1170,1135,1075,1018,955,914,850,753,695；1H-NMR(300MHz,DMSO-d6):δ/ppm= 12.52(s,1H),8.30(m,1H),8.23(m,1H),8.01(m,1H),4.39(m,1H),4.20(m,1H),3.73(m, 2H), 3.53 (m, J=6.0Hz, 1H), 2.88 (m, 1H), 2.43 (m, 2H), 2.03 (s, 3H), 1.93 (m, 1H), 1.78 (m, 1H), 1.35 (d, J=6.0Hz, 3H), 1.27 (m, 3H).
Embodiment 5 prepares Boc-Met-Gly-OBzl (2b)
According to the method for embodiment 1, obtained by 4g (16.0mmol) Boc-Met and 6g (16.8mmol) TosGly-OBz 7.1g (81%) title compound, it is yellow oil.
Embodiment 6 prepares Boc-Met-Ile-OBzl (2c)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 7.1g (16.8mmol) TosIle-OBzl 7.2g (82%) title compound is obtained, is yellow oil.
Embodiment 7 prepares Boc-Met-Leu-OBzl (2d)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 7.2g (16.8mmol) TosLeu-OBzl 7.6g (82%) title compound is obtained, is yellow oil.
Embodiment 8 prepares Boc-Met-Phe-OBzl (2e)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 8.82g (16.9mmol) HClPhe-OBzl 8g (85%) title compound is obtained, is yellow oil.
Embodiment 9 prepares Boc-Met-Trp-OBzl (2f)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 5.9g (16.8mmol) HClTrp-OBzl 6.5g (75%) title compound is obtained, is yellow oil.
Embodiment 10 prepares Boc-Met-Val-OBzl (2g)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 6.7g (16.8mmol) TosVal-OBzl 7.5g (86%) title compound is obtained, is yellow oil.
Embodiment 11 prepares Boc-Met-Tyr-OBzl (2h)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 5.5g (16.8mmol) HClTyr-OBzl 7g (82%) title compound is obtained, is yellow oil.
Embodiment 12 prepares Boc-Met-Asp (OBzl)-OBzl (2i)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 8.5g (16.8mmol) TosAsp (OBzl)-OBzl obtains 7g (81%) title compound, is yellow oil.
Embodiment 13 prepares Boc-Met-Glu (OBzl)-OBzl (2j)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 6.4g (16.8mmol) HClGlu (OBzl)-OBzl obtains 7g (82%) title compound, is yellow oil.
Embodiment 14 prepares Boc-Met-Pro-OBzl (2k)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 4.3g (16.8mmol) HClPro-OBzl 7g (83%) title compound is obtained, is yellow oil.
Embodiment 15 prepares Boc-Met-Met-OBzl (2l)
According to the method for embodiment 1, by 4g (16.0mmol) Boc-Met and 6.58g (16.8mmol) TosMet-OBzl 7.5g (84%) title compound is obtained, is yellow oil.
Embodiment 16 prepares HClMet-Ala-OBzl (3b)
According to the method for embodiment 2, title compound is obtained by 7g (16.0mmol) Boc-Met-Ala-OBzl, is yellow Grease.
Embodiment 17 prepares HClMet-Ile-OBzl (3c)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Ile-OBzl, is yellow oil Shape thing.
Embodiment 18 prepares HClMet-Leu-OBzl (3d)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Leu-OBzl, is yellow oil Shape thing.
Embodiment 19 prepares HClMet-Phe-OBzl (3e)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Phe-OBzl, is yellow oil Shape thing.
Embodiment 20 prepares HClMet-Trp-OBzl (3f)
According to the method for embodiment 2, title compound is obtained by 6.5g (16mmol) Boc-Met-Trp-OBzl, is yellow Grease.
Embodiment 21 prepares HClMet-Val-OBzl (3g)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Val-OBzl, is yellow oil Shape thing.
Embodiment 22 prepares HClMet-Tyr-OBzl (3h)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Tyr-OBzl, is yellow oil Shape thing.
Embodiment 23 prepares HClMet-Asp (OBzl)-OBzl (3i)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Asp (OBzl)-OBzl, is Yellow oil.
Embodiment 24 prepares HClMet-Glu-OBzl (3j)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Glu (OBzl)-OBzl, is Yellow oil.
Embodiment 25 prepares HClMet-Pro-OBzl (3k)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Pro-OBzl, is yellow oil Shape thing.
Embodiment 26 prepares HClMet-Met-OBzl (3l)
According to the method for embodiment 2, title compound is obtained by 7g (16mmol) Boc-Met-Met-OBzl, is yellow oil Shape thing.
Embodiment 27 prepares Tiopronin acyl-Met-Gly-OBzl (4b)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 8g (16mmol) HClMet-Gly- OBzl obtains 1.1g (15.6%) title compound, is colorless solid.ESI-MS(m/e):442[M+H]+；Mp:137-138℃； IR(cm-1):3274,3079,2924,1739,1548,1515,1439,1379,1298, 1186,1170,1019,947,698；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.45 (m, 1H), 8.21 (m, 1H), 8.09 (m, 1H), 7.36 (m, 5H), 5.12 (s, 2H), 4.39 (m, 1H), 3.90 (m, 2H), 3.82 (m, 2H), 3.53 (m, J= 6.0Hz, 1H), 2.88 (m, 1H), 2.45 (m, 2H), 2.01 (s, 3H), 1.80 (m, 2H), 1.34 (d, J=6.0Hz, 3H).
Embodiment 28 prepares Tiopronin acyl-Met-Ile-OBzl (4c)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Ile- OBzl obtains 1.7g (21.4%) title compound, is colorless solid.ESI-MS(m/e):498[M+H]+；Mp:93.8-94.6 ℃； IR(cm-1):3277,3070,2963,2924,2875,1736,1522,1443, 1380,1176,1142,989,740,697；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.27 (m, 2H), 8.00 (m, 1H), 7.36 (m, 5H), 5.11 (m, 2H), 4.46 (m, 1H), 4.22 (m, 1H), 3.73 (m, 2H), 3.54 (m, J=6.0Hz, 1H), 2.87 (m, 1H), 2.39 (m, 2H), 1.99 (s, 3H), 1.78 (m, 3H), 1.34 (d, J=6.0Hz, 3H), 1.18 (m, 2H),0.83(m,3H),0.80(m,3H)。
Embodiment 29 prepares Tiopronin acyl-Met-Leu-OBzl (4d)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Leu- OBzl obtains 1.3g (16.3%) title compound, is colorless solid.ESI-MS(m/e):498[M+H]+；Mp:100-101℃； IR(cm-1):3284,3066,2922,1733,1531,1446,1392,1309,1189, 1080,954,739,696；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.38 (m, 1H), 8.22 (m, 1H), 8.01 (m, 1H), 7.35 (m, 5H), 5.11 (s, 2H), 4.40 (m, 1H), 4.36 (m, 1H), 3.76 (m, 2H), 3.54 (m, J=6.0Hz, 1H), 2.43 (m, 2H), 1.99 (s, 3H), 1.83 (m, 2H), 1.59 (m, 3H), 1.34 (d, J=6.0Hz, 3H), 0.88 (d, J =6.0Hz, 3H), 0.82 (d, J=6.0Hz, 3H).
Embodiment 30 prepares Tiopronin acyl-Met-Phe-OBzl (4e)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Phe- OBzl obtains 2.1g (24.7%) title compound, is colorless solid.ESI-MS(m/e):532[M+H]+；Mp:113-114℃； IR(cm-1):3286,3066,2920,1732,1537,1439,1340,1216,1192, 1078,1012,1012,736,695,594；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.52 (m, 1H), 8.25 (m, 1H),8.04(m,1H),7.25(m,10H),5.05(m,2H),4.50(m,1H),4.40(m,1H),3.72(m,2H),3.56 (m, J=6.0Hz, 1H), 3.01 (m, 2H), 2.36 (m, 2H), 1.98 (s, 3H), 1.81 (m, 1H), 1.70 (m, 1H), 1.34 (d, J=6.0Hz, 3H).
Embodiment 31 prepares Tiopronin acyl-Met-Trp-OBzl (4f)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Trp- OBzl obtains 2.2g (24.1%) title compound, is colorless solid.ESI-MS(m/e):571[M+H]+；Mp:132-133℃； IR(cm-1):3287,3066,2921,1731,1537,1438,1338,1216,1195, 1078,1011,736,696,596；1H-NMR(300MHz,DMSO-d6):δ/ppm=10.86 (s, 1H), 8.51 (m, 1H), 8.28(m,1H),8.03(m,1H),7.30(m,10H),5.04(m,2H),4.56(m,1H),4.47(m,1H),3.75(m, 3H), 3.71 (m, J=3.0Hz, 1H), 3.15 (m, 2H), 2.37 (m, 2H), 1.98 (m, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.33 (d, J=3.0Hz, 3H).
Embodiment 32 prepares Tiopronin acyl-Met-Val-OBzl (4g)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Val- OBzl obtains 1.1g (14.3%) title compound, is colorless solid.ESI-MS(m/e):484[M+H]+；Mp:75-76℃； IR(cm-1):3286,3067,2964,2927,1738,1531,1442,1390,1310, 1187,1146,1001,738,695；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.23 (m, 2H), 8.03 (m, 1H), 7.35 (m, 5H), 5.13 (m, 2H), 4.47 (m, 1H), 4.16 (m, 1H), 3.73 (m, 2H), 3.54 (m, J=6.0Hz, 1H), 2.87 (m, 1H), 2.41 (m, 2H), 2.08 (m, 1H), 1.99 (s, 3H), 1.83 (m, 2H), 1.35 (d, J=6.0Hz, 3H), 0.88 (d, J=3.0Hz, 3H), 0.86 (d, J=3.0Hz, 3H).
Embodiment 33 prepares Tiopronin acyl-Met-Tyr-OBzl (4h)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Tyr- OBzl obtains 2.0g (25.8%) title compound, is colorless solid.ESI-MS(m/e):486[M+H]+；Mp:127-128℃； IR(cm-1):3279,3069,2918,1718,1544,1441,1373,1287,1218, 1172,1105,1072,1013,827,730,692；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.32 (m, 2H), 7.98 (m, 1H), 7.30 (m, 5H), 6.98 (d, J=6.0Hz, 2H), 6.64 (d, J=6.0Hz, 2H), 5.05 (m, 2H), 4.41 (m, 2H), 3.72 (m, 2H), 3.53 (m, J=6.0Hz, 1H), 2.89 (m, 3H), 2.35 (m, 2H), 1.99 (s, 3H), 1.72 (m, 2H), 1.34 (d, J=6.0Hz, 3H).
Embodiment 34 prepares Tiopronin acyl-Met-Asp (OBzl)-OBzl (4i)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Asp (OBzl)-OBzl obtains 1.7g (18.1%) title compound, is colorless solid.ESI-MS(m/e):590[M+H]+；Mp: 134-135℃；IR(cm-1):3290,3065,2923,1730,1536,1441,1388, 1338,1212,1074,1017,905,739,695,600；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.56 (m, 1H), 8.22(m,1H),8.04(m,1H),7.34(m,10H),5.09(s,4H),4.74(m,1H),4.39(m,1H),3.774(m, 2H), 3.54 (m, J=6.0Hz, 1H), 2.87 (m, 3H), 2.41 (m, 2H), 1.99 (s, 3H), 1.87 (m, 1H), 1.74 (m, 1H), 1.33 (m, J=6.0Hz, 3H).
Embodiment 35 prepares Tiopronin acyl-Met-Glu (OBzl)-OBzl (4j)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Glu (OBzl)-OBzl obtains 2.1g (21.8%) title compound, is colorless solid.ESI-MS(m/e):604[M+H]+；Mp:95- 96℃；IR(cm-1):3283,3065,2922,1731,1537,1446,1391,1309, 1172,1120,1080,962,909,739,696；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.42 (m, 1H), 8.21 (m, 1H), 8.04 (m, 1H), 7.34 (m, 10H), 5.11 (m, 4H), 4.37 (m, 2H), 3.73 (m, 2H), 3.54 (m, J= 6.0Hz, 1H), 2.85 (m, 1H), 2.43 (m, 4H), 1.94 (m, 8H), 1.33 (d, J=6.0Hz, 3H).
Embodiment 36 prepares Tiopronin acyl-Met-Pro-OBzl (4k)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Pro- OBzl obtains 2.0g (25.9%) title compound, is colorless solid.ESI-MS(m/e):482[M+H]+；Mp:149-152℃； 1H-NMR(300MHz,DMSO-d6):δ/ppm=8.18 (m, 2H), 7.35 (m, 5H), 5.11 (m, 2H), 4.67 (m, 1H), 4.40 (m, 1H), 3.71 (m, 2H), 3.62 (m, J=6.0Hz, 1H), 2.86 (m, 1H), 2.45(m,2H),2.30(m,1H),2.19(m,1H),1.97(s,3H),1.92(m,2H),1.88(m,3H),1.71(m,1H), 1.32 (d, J=6.0Hz, 1H).
Embodiment 37 prepares Tiopronin acyl-Met-Met-OBzl (4l)
According to the method for embodiment 3, by 2.6g (16.0mmol) Tiopronins and 7g (16mmol) HClMet-Met- OBzl obtains 1.7g (20.6%) title compound, is colorless solid.ESI-MS(m/e):516[M+H]+；Mp:82-83℃； IR(cm-1):3284,3065,2918,1731,1532,1440,1392,1189,1124, 1080,1018,954,908,750,697,597；1H-NMR(300MHz,DMSO-d6):δ/ppm=8.44 (m, 1H), 8.23 (m, 1H), 8.05 (m, 1H), 7.37 (m, 5H), 5.12 (s, 2H), 4.41 (m, 2H), 3.72 (m, 2H), 3.54 (m, J=6.0Hz, 1H), 2.86 (m, 1H), 2.44 (m, 4H), 2.01 (s, 3H), 2.00 (s, 3H), 1.79 (m, 4H), 1.35 (d, J=6.0Hz, 3H).
Embodiment 38 prepares Tiopronin acyl-Met-Gly (5b)
According to the method for embodiment 4,50mg (21%) is obtained by 300mg (0.61mmol) Tiopronin acyl-Met-Gly-OBzl Title compound, it is colorless solid.ESI-MS(m/e):350[M-H]-；Mp:81-82℃； IR(cm-1):3285,3078,2919,1733,1537,1405,1205,1020,666；1H-NMR(300MHz,DMSO-d6):δ/ Ppm=12.53 (s, 1H), 8.29 (m, 1H), 8.22 (m, 1H), 8.06 (m, 1H), 4.38 (m, 1H), 3.76 (m, 4H), 3.58 (m, J=6.0Hz, 1H), 2.88 (m, 1H), 2.46 (m, 2H), 2.03 (s, 3H), 1.92 (m, 1H), 1.78 (m, 1H), 1.35 (d, J=6.0Hz, 3H).
Embodiment 39 prepares Tiopronin acyl-Met-Ile (5c)
According to the method for embodiment 4,61mg (22.9%) is obtained by 300mg (0.64mmol) Tiopronin acyl-Met-Ile-OBzl Title compound, it is colorless solid.ESI-MS(m/e):406[M-H]-；Mp:90-92℃；IR (cm-1):3293,3067,2964,2928,2875,1731,1519,1445,1383,1192,1143,1017,738,696；1H- NMR(300MHz,DMSO-d6):δ/ppm=12.59 (s, 1H), 8.24 (m, 1H), 8.06 (m, 2H), 4.46 (m, 1H), 4.13 (m, 1H), 3.76 (m, 2H), 3.57 (m, J=6.0Hz, 1H), 2.87 (m, 1H), 2.46 (m, 2H), 2.02 (s, 3H), 1.84 (m, 3H), 1.42 (m, 1H), 1.35 (d, J=6.0Hz, 3H), 1.21 (m, 1H), 0.86 (m, 3H), 0.83 (m, 3H).
Embodiment 40 prepares Tiopronin acyl-Met-Leu (5d)
According to the method for embodiment 3,45mg (20%) is obtained by 300mg (0.64mmol) Tiopronin acyl-Met-Leu-OBzl Title compound, it is colorless solid.ESI-MS(m/e):406[M-H]-；Mp:109-112℃； IR(cm-1):3286,3072,2927,1722,1411,1207,1020,636；1H-NMR(300MHz,DMSO-d6):δ/ppm= 12.50 (s, 1H), 8.21 (m, 2H), 7.98 (m, 1H), 4.44 (m, 1H), 4.26 (m, 1H), 3.75 (m, 2H), 3.57 (m, J= 6.0Hz,1H),2.87(m,1H),2.43(m,2H),2.03(s,3H),1.83(m,3H),1.64(m,1H),1.52(m,2H), 1.35 (d, J=6.0Hz, 3H), 0.89 (d, J=6.0Hz, 3H), 0.84 (d, J=6.0Hz, 3H).
Embodiment 41 prepares Tiopronin acyl-Met-Phe (5e)
According to the method for embodiment 4,44mg (19%) is obtained by 300mg (0.62mmol) Tiopronin acyl-Met-Phe-OBzl Title compound, it is colorless solid.ESI-MS(m/e):440[M-H]-；Mp:98-99℃；IR (cm-1):3294,3062,2922,1726,1440,1214,1018,738,699；1H-NMR(300MHz,DMSO-d6):δ/ppm =12.50 (s, 1H), 8.21 (m, 2H), 7.98 (m, 1H), 4.44 (m, 1H), 4.26 (m, 1H), 3.75 (m, 2H), 3.57 (m, J =6.0Hz, 1H), 3.08 (m, 1H), 2.87 (m, 2H), 2.43 (m, 2H), 2.03 (s, 3H), 1.83 (m, 3H), 1.35 (d, J= 6.0Hz,3H)。
Embodiment 42 prepares Tiopronin acyl-Met-Trp (5f)
According to the method for embodiment 4,130mg (55%) is obtained by 300mg (0.58mmol) Tiopronin acyl-Met-Trp-OBzl Title compound, it is colorless solid.ESI-MS(m/e):479[M-H]-；Mp:112-114℃； IR(cm-1):3078,2966,2920,2560,1736,1438,1407,1345,1186,1109,730,638,606；1H-NMR (300MHz,DMSO-d6):δ (ppm)=12.50 (s, 1H), 10.86 (s, 1H), 8.51 (m, 1H), 8.28 (m, 1H), 8.03 (m, 1H), 7.30 (m, 5H), 4.56 (m, 1H), 4.47 (m, 1H), 3.75 (m, 3H), 3.71 (m, J=3.0Hz, 1H), 3.15 (m, 2H), 2.37 (m, 2H), 1.98 (m, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.33 (d, J=3.0Hz, 3H).
Embodiment 43 prepares Tiopronin acyl-Met-Val (5g)
According to the method for embodiment 4,63mg (27%) is obtained by 300mg (0.60mmol) Tiopronin acyl-Met-Val-OBzl Title compound, it is colorless solid.ESI-MS(m/e):392[M-H]-；Mp:133-135℃； IR(cm-1):3296,3078,2967,2926,1730,1405,1204,1077,1019,635；1H-NMR(300MHz,DMSO- d6):δ/ppm=12.50 (s, 1H), 8.23 (m, 2H), 8.03 (m, 1H), 4.47 (m, 1H), 4.16 (m, 1H), 3.73 (m, 2H), 3.54 (m, J=6.0Hz, 1H), 2.87 (m, 1H), 2.41 (m, 2H), 2.08 (m, 1H), 1.99 (s, 3H), 1.83 (m, 2H), 1.35 (d, J=6.0Hz, 3H), 0.88 (d, J=3.0Hz, 3H), 0.86 (d, J=3.0Hz, 3H).
Embodiment 44 prepares Tiopronin acyl-Met-Tyr (5h)
According to the method for embodiment 4,180mg (75%) is obtained by 300mg (0.59mmol) Tiopronin acyl-Met-Tyr-OBzl Title compound, it is colorless solid.ESI-MS(m/e):394[M-H]-；Mp:89-92℃； IR(cm-1):3299,3064,2921,1739,1632,1442,1409,1337,1315,1208,1018,956,913,820, 753,695；1H-NMR(300MHz,DMSO-d6):δ/ppm=12.64 (s, 1H), 9.17 (s, 1H), 8.21 (m, 2H), 7.94 (m, 1H), 7.00 (m, 2H), 6.71 (m, 2H), 4.35 (m, 2H), 3.71 (m, 2H), 3.52 (m, J=6.0Hz, 1H), 2.88 (m, 2H), 2.39 (m, 2H), 1.93 (s, 3H), 1.83 (m, 3H), 1.35 (d, J=6.0Hz, 3H).
Embodiment 45 prepares Tiopronin acyl-Met-Asp (5i)
According to the method for embodiment 4,100mg is obtained by 300mg (0.55mmol) Tiopronin acyl-Met-Asp (OBzl)-OBzl (42%) title compound, it is colorless solid.ESI-MS(m/e):406[M-H]-；Mp:74-76℃； IR(cm-1):3294,3076,2923,1722,1411,1209,1021,632；1H-NMR(300MHz,DMSO- d6):δ/ppm=12.58 (s, 1H), 8.33 (m, 1H), 8.22 (m, 1H), 8.03 (m, 1H), 4.50 (m, 1H), 4.38 (m, 1H), 3.72 (m, 2H), 3.51 (m, J=6.0Hz, 1H), 3.13 (m, 1H), 2.86 (m, 1H), 2.68 (m, 1H), 2.53 (m, 1H), 2.40 (m, 2H), 1.99 (s, 3H), 1.86 (m, 2H), 1.74 (m, 1H), 1.35 (d, J=6.0Hz, 3H).
Embodiment 46 prepares Tiopronin acyl-Met-Glu (5j)
According to the method for embodiment 4,102mg is obtained by 300mg (0.54mmol) Tiopronin acyl-Met-Glu (OBzl)-OBzl (43%) title compound, it is colorless solid.ESI-MS(m/e):422[M-H]-；Mp:97-98℃； IR(cm-1):3286,3077,2920,1733,1532,1409,1206,1019,666；1H-NMR(300MHz, DMSO-d6):δ/ppm=7.51 (d, J=7.8Hz, 1H), 7.37 (m, 10H), 6.55 (d, J=7.8Hz, 1H), 6.13 (m, J =7.2Hz, 1H), 5.20 (m, 4H), 4.71 (m, 2H), 4.50 (s, 1H), 2.91 (dd, J1=8.7Hz, J2=3.0Hz, 1H), 2.51(m,5H),2.06(m,11H),1.47(s,9H)。
Embodiment 47 prepares Tiopronin acyl-Met-Pro (5k)
According to the method for embodiment 4,65mg (33%) is obtained by 300mg (0.65mmol) Tiopronin acyl-Met-Pro-OBzl Title compound, it is colorless solid.ESI-MS(m/e):390[M-H]-；Mp:86-88℃； IR(cm-1):3286,3068,2922,1731,1526,1444,1332,1184,1018,659；1H-NMR(300MHz,DMSO- d6):δ/ppm=12.50 (s, 1H), 8.17 (m, 2H), 4.67 (m, 1H), 4.25 (m, 1H), 3.72 (m, 2H), 3.51 (m, J= 6.0Hz, 1H), 2.86 (m, 1H), 2.39 (m, 2H), 2.15 (m, 1H), 2.04 (s, 3H), 1.87 (m, 6H), 1.34 (d, J= 6.0Hz,3H)。
Embodiment 48 prepares Tiopronin acyl-Met-Met (5l)
According to the method for embodiment 4,105mg (45%) is obtained by 300mg (0.64mmol) Tiopronin acyl-Met-Met-OBzl Title compound, it is colorless solid.ESI-MS(m/e):424[M-H]-；Mp:107-109℃； IR(cm-1):3286,3077,2919,1731,1435,1206,1020,666；1H-NMR(300MHz,DMSO-d6):δ/ppm= 12.66 (s, 1H), 8.25 (m, 2H), 8.03 (m, 1H), 4.39 (m, 1H), 4.28 (m, 1H), 3.72 (m, 2H), 3.55 (m, J= 6.0Hz 1H), 2.88 (m, 1H), 2.45 (m, 4H), 2.03 (s, 3H), 1.88 (m, 4H), 1.34 (d, J=6.0Hz, 3H).
Embodiment 49 evaluates lead discharging activity inside oral 7 days of compound 5a-l
The healthy ICR male mices that 170 body weight are 18-20g are taken, it is water-soluble that intraperitoneal injection with deionized water is made into lead acetate Liquid, dosage are 8.2mgPb (CH3CO2)2·3H2O/kg, continuous injection 7 days, stops contamination, experimental animal is randomly divided into 17 Group, every group 10.All animals start gavage after 48h, and positive controls penicillamine (D-PA) dosage is 400 μm of ol/ kg.Compound 5a-l given lows are 4.9 μm of ol/kg, and Tiopronin acyl-Met group given lows are 49 μm of ol/kg,；General sieve of sulphur Peaceful given low is that 490 μm of ol/kg are made up a prescription with physiological saline, control group physiological saline gavage, every administration 0.2mL/20g.
After being administered daily, collect mouse 24h urines and excrement, continue 7 days, the urine of daily every group of mouse, excrement respectively as One sample.After last time administration 24h, after excision eyeball of mouse takes whole blood, take off neck and put to death, observation internal organ change, separate And brain is taken out, heart, liver, kidney, spleen and left femur are used as sample in the lump with whole blood.
All biological specimens use HNO3∶H2O2(2: 1) nitrification in MARS-xpress microwave nitre solution instrument is extremely molten into clarifying Liquid, it is transferred in 10mL volumetric flasks, with tri-distilled water constant volume, with VarianICP-710ES inductively coupled plasma spectrophotometers The content of lead and other indispensable elements in sample
Concentration of metal ions in VarianICP-710ES inductively coupled plasma atomic emissions institute test sample sheet is entered into line number According to processing, lead content in every gram of sample (urine is lead content in every milliliter of sample) is calculated, carries out counting t inspections.In each tissue The content (μ g/g) of lead be included in Tables 1 and 2, the content (μ g/g excrement or urine μ g/mL) of lead is included in table 3 in excrement and urine.
The compound 5a-l oral medications of table 1 after 7 days in the heart, brain, blood and kidney lead tolerance (μ g lead/g organs)
N=10；A) p is compared with physiological saline<0.05, with penicillamine than p ＞ 0.05, with Tiopronin acyl-Met than p ＞ 0.05；B) p is compared with physiological saline<0.01, with penicillamine than p ＞ 0.05, with Tiopronin acyl-Met than p ＞ 0.05；C) it is and raw Manage brine ratio p<0.01, compare p with penicillamine<0.01, compare p with Tiopronin acyl-Met<0.01；D) p is compared with physiological saline< 0.01, with penicillamine than p ＞ 0.05, compare p with Tiopronin acyl-Met<0.05.
The compound 5a-l oral medications of table 2 after 7 days in liver, spleen, bone lead tolerance (μ g lead/g organs)
N=10；A) p is compared with physiological saline<0.05, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met>0.05； B) p is compared with physiological saline<0.01, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met>0.05；C) p is compared with physiology salt< 0.01, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met<0.05.
The compound 5a-l oral medications of table 3 after 7 days in urine and excrement lead tolerance (mean value ± SD μ g lead/mL urine, Value ± SD μ g lead/g excrement)
N=10, a) compare p with physiological saline<0.05；B) p is compared with physiological saline<0.01.
Embodiment 50 evaluates the compound 5a-l influences to trace element in oral 7 days
Influence of the compound 5a-l treatments to indispensable element is also evaluated in the present invention.By VarianICP-710ES inductance couplings The concentration for closing various metallic elements in ICP institute test sample sheet carries out data processing, carries out t inspections, the results are shown in Table 4- 12.As a result show, compound 5a-l treatments have no significant effect to indispensable element.
4 compound 5a-l oral medications of table 7 days to mouse core trace element influence (The μ g/g hearts)
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
5 compound 5a-l oral medications of table 7 days to Mouse Liver trace element influence (μ g/g livers)
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g spleens) to mice spleen trace element in 7 days of 6 compound 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g kidneys) to Mouse Kidney trace element in 7 days of 7 compound 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g brains) to mouse brain trace element in 7 days of 8 compound 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g bones) to mouse bron-exposed wound in 7 days of 9 compound 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g blood) to mouse blood trace element in 7 days of 10 compound 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/mL urine) to mouse retention trace element in 7 days of 11 compound 5a-l oral medications of table
N=10
The influence (mean value ± SD μ g/g excrement) to mouse excrement trace element in 7 days of 12 compound 5a-l oral medications of table
N=10
Embodiment 51 evaluates the 5a-l lead dischargings of oral 20 days activity
The healthy ICR male mices that 160 body weight are 18-20g are taken, it is water-soluble that intraperitoneal injection with deionized water is made into lead acetate Liquid, dosage are 8.2mgPb (CH3CO2)2·3H2O/kg, continuous injection 7 days, stops contamination, experimental animal is randomly divided into 16 Group, every group 10.All animals start gavage after 48h, and positive controls penicillamine dosage is 400 μm of ol/kg.5a-l Group given low is 4.9 μm of ol/kg, Tiopronin acyl-Met group gavages, is made up a prescription with physiological saline, control group is filled with physiological saline Stomach, every administration 0.2mL/20g.
It is administered daily, continues 20 days, last time is administered after 24h, after excision eyeball of mouse takes whole blood, is taken off neck and is put to death, Observation internal organ change, separates and takes out brain, heart, liver, kidney, spleen and left femur, sample is used as in the lump with whole blood.
All biological specimens use HNO3∶H2O2(2: 1) nitrification in MARS-xpress microwave nitre solution instrument is extremely molten into clarifying Liquid, it is transferred in 10mL volumetric flasks, with tri-distilled water constant volume, with VarianICP-710ES inductively coupled plasma spectrophotometers The content of lead and other indispensable elements in sample.
Concentration of metal ions in VarianICP-710ES inductively coupled plasma atomic emissions institute test sample sheet is entered into line number According to processing, lead content in every gram of sample is calculated, carries out counting t inspections.The content (μ g/g) of lead in each tissue is included in table 14 With table 15.
Lead tolerance (mean value ± SD μ g lead/g organ) of the 14 5a-l oral medications of table after 20 days in the heart, brain, blood and liver
N=10；A) p is compared with physiological saline<0.05, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met>0.05； B) p is compared with physiological saline<0.01, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met>0.05；C) with physiological saline ratio p<0.01, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met<0.05；D) p is compared with physiological saline<0.01, with mould Amine compares p>0.05, compare p with Tiopronin acyl-Met<0.01；E) p compared with physiological saline group<0.01, compare p with penicillamine< 0.05, compare p with Tiopronin acyl-Met<0.01.
Lead tolerance (mean value ± SD μ g lead/g organ) of the 15 5a-l oral medications of table after 20 days in kidney, spleen, bone
N=10；A) p is compared with physiological saline<0.05, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met>0.05； B) p is compared with physiological saline<0.01, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met>0.05；C) with physiological saline ratio p<0.01, compare p with penicillamine>0.05, compare p with Tiopronin acyl-Met<0.05；D) p is compared with physiological saline<0.05, with mould Amine compares p<0.05, compare p with Tiopronin acyl-Met>0.01.
Embodiment 53 evaluates the compound 5a-l influences to trace element in oral 20 days
Influence of the compound 5a-l treatments to indispensable element is also evaluated in the present invention.By VarianICP-710ES inductance couplings The concentration for closing various metallic elements in ICP institute test sample sheet carries out data processing, carries out variance analysis, the results are shown in Table 16 to table 22.As a result show, compound 5a-l treatments have no significant effect to indispensable element.
The influence (the mean value ± SD μ g/g hearts) to mouse core trace element in 20 days of 16 5a-l oral medications of table
N=10；A) with physiological saline ratio, p<0.05；B) with physiological saline ratio, p<0.01；C) with physiological saline ratio, p> 0.05。
The influence (mean value ± SD μ g/g spleens) to mice spleen trace element in 20 days of 17 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g kidneys) to Mouse Kidney trace element in 20 days of 18 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g brains) to mouse brain trace element in 20 days of 19 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g bones) to mouse bron-exposed wound in 20 days of 20 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g blood) to mouse blood trace element in 20 days of 21 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.
The influence (mean value ± SD μ g/g livers) to Mouse Liver trace element in 20 days of 22 5a-l oral medications of table
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01；C) p is compared with physiological saline>0.05.

Claims (3)

1. following formula Tiopronin acyl-Met-AA 12 kinds of compounds,
In formula, AA is selected from glycine residue, Valine residue, L-Leu residue, ILE residue, L-Aspartic acid Residue, Pidolidone residue, TYR residue, L-PROLINE residue, ALANINE residue, METHIONINE residue, L- benzene Alanine residue and L-Trp residue.
2. the Tiopronin acyl-Met-AA of claim 1 preparation method, this method include：
(1) dicyclohexylcarbodiimide, 1- hydroxy benzo triazoles catalysis under by standard method prepare 12 kinds of Boc-Met- AA-OBzl；
(2) 12 kinds of Boc-Met-AA-OBzl 0 DEG C of de- Boc, change into 12 kinds in the ethyl acetate solution of 4N hydrogen chloride HCl·Met-AA-OBzl；
(3) dicyclohexylcarbodiimide, 1- hydroxy benzo triazoles catalysis under prepare 12 kinds of Tiopronin acyl-Met-AA- OBzl；
(4) 12 kinds of Tiopronin acyl-Met-AA-OBzl the 2N NaOH aqueous solution effect under change into 12 kinds of Tiopronin acyls- Met-AA。
3. 12 kinds of Tiopronin acyl-Met-AA of claim 1 application in lead discharging medicine is prepared.
CN201610422889.1A 2016-06-14 2016-06-14 Tiopronin acyl-Met-AA, and synthesis, activity and application thereof Expired - Fee Related CN107501390B (en)

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CN1850797A (en) * 2006-05-18 2006-10-25 武汉远大制药集团有限公司 Tiopronin amino salt, and its preparing method
CN1887859A (en) * 2006-07-13 2007-01-03 武汉远大制药集团有限公司 Tiopronin amidate and its prepn
WO2012058269A2 (en) * 2010-10-29 2012-05-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods of treating cancer and other diseases
CN102898339A (en) * 2012-10-29 2013-01-30 苏州二叶制药有限公司 Method for preparing tiopronin
CN105198960A (en) * 2014-06-13 2015-12-30 首都医科大学 Imidazopyridine-6-formyl-Met-AA-OBzl and synthesis, activity and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1850797A (en) * 2006-05-18 2006-10-25 武汉远大制药集团有限公司 Tiopronin amino salt, and its preparing method
CN1887859A (en) * 2006-07-13 2007-01-03 武汉远大制药集团有限公司 Tiopronin amidate and its prepn
WO2012058269A2 (en) * 2010-10-29 2012-05-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods of treating cancer and other diseases
CN102898339A (en) * 2012-10-29 2013-01-30 苏州二叶制药有限公司 Method for preparing tiopronin
CN105198960A (en) * 2014-06-13 2015-12-30 首都医科大学 Imidazopyridine-6-formyl-Met-AA-OBzl and synthesis, activity and application thereof

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