CN102942497A - Preparation and application of amino substituted carboxylic acid compounds - Google Patents

Preparation and application of amino substituted carboxylic acid compounds Download PDF

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CN102942497A
CN102942497A CN2012105203446A CN201210520344A CN102942497A CN 102942497 A CN102942497 A CN 102942497A CN 2012105203446 A CN2012105203446 A CN 2012105203446A CN 201210520344 A CN201210520344 A CN 201210520344A CN 102942497 A CN102942497 A CN 102942497A
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compound
metal
general formula
decorporation
carboxylic acid
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CN102942497B (en
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张邦乐
何炜
郭军
周四元
万宁
李骅
巨佳
张芳芳
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Fourth Military Medical University FMMU
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Abstract

The invention relates to two novel amino substituted carboxylic acid compounds and a preparation method thereof. The compounds can be used for the prevention and treatment of in-vivo metal poisoning and the preparation of metal decorporation medicaments and health products. The amino substituted carboxylic acid compounds combine the advantages of aminocarboxylic acid and phenolic hydroxyl; and the two novel chelators designed by effectively introducing carboxyl chelation groups onto the benzylic site of a benzene ring have fine metal poisoning prevention and treatment activity and metal decorporation activity. By adding the effective chelation groups on the benzylic site in the molecule chelation center, the nuclide ion bonding capability is enhanced, so that the compounds can be easily formed into stable complexes, thereby accelerating the in-vivo discharge and improving the decorporation effect and poisoning prevention and treatment effect of metal (especially uranium).

Description

Preparation and the application thereof of amino substituted carboxylic acid compounds
Affiliated technical field
The present invention relates to two class novel amino substituted carboxylic acid compounds and preparation method thereof, such material can be used for the preparation of in-vivo metal poisoning control and metal decorporation medicine and healthcare products.
Background technology
Nature exists Determination of multiple metal elements, some element is the necessary element of keeping HUMAN HEALTH such as iron, zinc, magnesium, calcium, but some metallic element is such as lead, mercury, arsenic, especially actinium series nucleic (uranium, thorium etc.) but can corrode HUMAN HEALTH, and must element is excessive also can affect HUMAN HEALTH.Because the application of radioelement is increasingly extensive, the radionuclide that causes because of radiocontamination enters in the body and long-term existence, also is a carcinogenic important factor.Using the discharge of the harmful metal elements in the sequestrant medicine acceleration bodies, reduce accumulating in human body, is important clinically methods for the treatment of.The compound that is used at present the metal decorporation has carboxylic propylhomoserin class (such as EDTA, DTPA-calcium trisodium pentetates etc.), (document is Current Medicinal Chemistry a) for sequestrant of pyrocatechol, pyridinone and ammonia carboxylic acid and phenolic hydroxyl group amalgamation (such as quinamic acid, bis-phenol amino acid) etc., 2005,12 (23), 2765-2770.b) Chinese radiological medicine and protection magazine, 1992,12 (2), 79-83; C) Acta Pharmaceutica Sinica, 1990,25 (10), 790-794; D) Chinese Pharmacological circular, 1996,12 (6), 503-505; E) Acta Pharmacologica Sinica, 1987,8 (3), 284-288; F) Shandong Medical University's journal, 1991,29 (4), 344-347; G) Chinese patent CN102727473A; H) patent US3509208; I) patent EP0840727A1).The sequestrant of ammonia carboxylic acid and phenolic hydroxyl group amalgamation has overcome some deficiency of EDTA, DTPA, strengthened the sequestering power of sequestrant, animal experimental observation strengthens to the decorporation effect of this class sequestrant to most metals, but has sequestrant now to nucleic, and especially the decorporation effect of uranium is still undesirable.Therefore, the decorporation medicine of seeking high-efficiency low-toxicity especially actinides Mobilization Agents thing is the research emphasis of domestic and international metal poisoning control always.
The structure of bis-phenol amino acid
Summary of the invention
The purpose of this invention is to provide two classes and have the amino substituted carboxylic acid compounds of pharmaceutical use and its pharmacy acceptable salt and preparation method thereof, further purpose is to provide the purposes of this compounds in preparation metal decorporation and metal poisoning control medicine and healthcare products.The present invention adopts ammonia carboxylic acid and phenolic hydroxyl group principle of hybridization, take 2-oxo acetic acid as connecting arm, by effectively introducing the carboxyl chelation group in phenyl ring benzyl position, make the easier and metal complex of its space length and phenolic hydroxyl group, strengthen chelating properties, obtain the brand-new amino substituted carboxylic acid class eccritic of two classes, and use it for metal decorporation and metal poisoning control medicine and healthcare products aspect.The advantage of the compounds of this invention is that it is more firm that itself and nucleic ionic bond are got, and forms stable complex compound by the effective chelation group in increase chelating center, discharges in the acceleration bodies, improves decorporation effect and the poisoning prevention effect of metal, especially uranium.
Compound structure general formula of the present invention (I) and (II) as follows
Figure BSA00000818574800021
Wherein:
R 1Be hydrogen, CH 2CO 2H;
R 2Be hydrogen, halogen, nitro, sulfonic group, carboxyl, C1～C6 alkoxyl group;
The above-claimed cpd pharmacy acceptable salt (compound general formula (I) and (II) in C0 2H and R 1Middle CO 2H salify CO 2R 3), described salt R 3Positively charged ion is alkali metal cation, alkaline earth metal cation, ammonium cation or basic aminoacids (such as arginine, Methionin or Histidine).
General formula compound (I) and preparation method (II):
General formula (I) and (II) shown in compound can prepare with the following method.Replacing o-phenol 1 as raw material, through with different mol ratio 2-oxo acetic acid, 2-Padil or iminodiethanoic acid at water; Ethanol; Or in water/ethanol through acid catalysis (HCl; HOAc; H 2S0 4H 3PO 4) or get serial target compound (I) and (II) without acid catalyzed reaction.(I) and during compou nd synthesis (II), because 2-oxo acetic acid activity is lower than formaldehyde, yield is higher during acid catalyzed reaction, and optimum condition is the acid catalyzed method of HOAc.(I) and (II) and corresponding mol ratio mineral alkali, organic bases or basic aminoacids at solvent methanol, ethanol, ether, tetrahydrofuran (THF), acetone, water, 1, the further pharmacy acceptable salt that gets of salt-forming reaction in the mixed solvent of 4-dioxane, DMF or above-mentioned solvent.
Syntheti c route as shown in the formula:
Figure BSA00000818574800031
Substituent R in the above reaction scheme 1, R 2Implication as previously mentioned.
The present invention provides formula (I) and (II) application of the medicinal compositions that forms as activeconstituents and the pharmaceutical carrier that is fit to or vehicle of compound or its pharmacy acceptable salt simultaneously.This compounds or its pharmacy acceptable salt be with after one or more physiologically acceptable vehicle or carrier (such as physiological saline, water for injection, starch, dextrin etc.) mix, and can be mixed with the medicinal compositions of injection, oral, oral cavity, hypogloeeis, implantation, local application or rectal administration.The preferred drug administration by injection of the present invention.
Amino substituted carboxylic acid compounds of the present invention or its pharmacy acceptable salt can be used for preparing metal poisoning control and in-vivo metal decorporation medicine and healthcare products.Test-results shows that above-claimed cpd has obvious metal poisoning control and decorporation effect.Wherein to Mn, Mg, Sr, Fe, Ba, Ni, U, especially the poisoning control of U and decorporation effect are better.The internal and external test method that detects metal poisoning control and metal decorporation effect is well known to a person skilled in the art, referring to background technology correlation technique document, is hereby incorporated by.And, in related embodiment, expect especially when the control use is united in metal poisoning, to can be used for method of the present invention and other medicines Synergistic treatment or reduce every kind of therapy dosage and poisonous side effect of medicine.
Embodiment
The invention will be further described below by embodiment, and the scope of the invention is not limited to following instance.
Embodiment 1 compound 2-carbonyl methylamino-2-2', and 3'-dihydroxy-benzene guanidine-acetic acid (4, R in the general formula (I) 1=H, R 2=H) preparation
In being housed, the 250mL round-bottomed flask of magnetic stirring apparatus and reflux adds o-phenol (1, R 2=H) 2.2g, 2-oxo acetic acid (2) 1.84g, 2-Padil (3, R 1=H) 1.65g and water 20mL mixes rear dropping 0.5mL acetic acid, heating reflux reaction (TLC endpoint detection), cooling, suction filtration, a small amount of washing with alcohol, dry white solid 2.26g.Y=47%; Mp:220 ℃ (decomposition); 1H NMR (DMSO-d 6, 400MHz): δ 7.41 (d, J=8.2Hz, 1H), 6.80-7.21 (m, 2H), 3.23-3.11 (m, 3H) ppm; MS (m/z, ESI -): 240[M-H] -IR (KBr): 3430,3021,2980,1687,1679,1219cm -1.
Embodiment 2 compound 2-N, N-two carbonyl methylamino-2-2', 3 '-dihydroxyl-5 '-anisole guanidine-acetic acid (5, R in the general formula (I) 1=CH 2CO 2H, R 2=OCH 3) preparation
In the 250mL round-bottomed flask of magnetic stirring apparatus and reflux is housed, add and replace o-phenol (1, R 2=4-methoxyl group) 11.2g, 2-oxo acetic acid (2) 7.36g, iminodiethanoic acid (3, R 1=CH 2CO 2H) 10.64g and water 80mL mix rear dropping 0.5mL acetic acid, heating reflux reaction (TLC endpoint detection), and cooling, suction filtration get white solid 6.9g.Y=53%; Mp:250 ℃ (decomposition); 1H NMR (DMSO-d 6, 400MHz): δ 7.35-7.24 (m, 2H), 3.87 (s, 3H), 3.43 (s, 1H), 3.32-3.21 (m, 4H) ppm; MS (m/z, ESI -): 328[M-H] -IR (KBr): 3430,3052,2992,2635,1695,1637,1210cm -1.
Embodiment 3 compounds 2,2'-N, N-two carbonyl methylaminos-2 ', 3 '-dihydroxyl 1', 4 '-phenyl diacetic acid (6, R in the general formula (II) 1=CH 2CO 2H, R 2=H) preparation
In being housed, the 250mL round-bottomed flask of magnetic stirring apparatus and reflux adds o-phenol (1, R 2=H) 4.4g, 2-oxo acetic acid (2) 7.36g, iminodiethanoic acid (3, R 1=CH 2CO 2H) 10.64g and water 70mL mix rear dropping 0.5mL acetic acid, heating reflux reaction (TLC endpoint detection), and cooling, suction filtration get white solid 6.8g.Y=70%; Mp:250 ℃ (decomposition); 1H NMR (DMSO-d 6, 400MHz): δ 7.42 (d, J=8.6Hz, 2H), 3.41 (s, 2H), 3.40-3.23 (m, 8H) ppm; MS (m/z, ESI -): 487[M-H] -IR (KBr): 3435,3052,2987,2685,1701,1629,1265cm -1.
Embodiment 4 formulas (I) and (II) compound sodium salt synthetic
In the 50mL of drying round-bottomed flask, add compound 4 (0.24g) and methyl alcohol 10mL.Cool the temperature to 0 ℃-5 ℃ under the ice bath, add sodium bicarbonate (0.24g, 1.3eq), stir lower reaction recession in 0.5 hour deicing and bathe.Continue reaction 6 hours under the normal temperature.30 ℃ remove solvent under reduced pressure.Add the 20mL ether, vibration, suction filtration, the dry white solid disodium salt 0.25g that gets.Yield 88%; Mp:250 ℃ of (decomposition) .IR (KBr): 3024,2925,2358,2343,1665,1092,768cm -1. the same process take compound 5,6 as raw material, adds sodium bicarbonate (1.3eq) and can make corresponding sodium salt target compound.
Other amino substituted carboxylic acid compounds (general formula (I) and (II)) and salt product make with reference to above-described embodiment method, as replacing the mineral alkali sodium bicarbonate with general formula (I) with organic bases or basic aminoacids and (II) can getting other pharmaceutically receivable salt when reacting.
Embodiment 5 amino substituted carboxylic acid compounds pharmacodynamic evaluations
1, animal detoxification experiment
Adopt kunming mice, body weight 18-22g, random packet, 10 every group, male and female half and half.Behind the abdominal injection various dose metal-salt immediately abdominal injection give pharmacological agent, model group is with the method injecting normal saline.Mouse freely ingests and drinks water, and observes mouse 7 days survival number and survival time.
2, decorporation test
Adopt wistar rat (female), body weight 150-180g, random packet, 6 every group.Every mouse give with uranyl nitrate 500mg/kg after intraperitoneal injection of drugs immediately, blank group injecting normal saline.Laboratory animal places in the metabolic cage, freely ingests and drinks water, and collects respectively 48 hours urine, measures urine uranium output.
3, the statistical procedures of experimental data
The experimental data value of averaging and variance are calculated, and more all adopt the t-check between two groups.
4, experimental result
Above-mentioned experimental result shows, amino substituted carboxylic acid compounds has preferably detoxifying effect to trial metal poisoning, 7 days animals survived number is obviously increased, wherein compound 5,6 and 8 detoxifcation are evident in efficacy, compound 6 and 8 pairs of uranyl nitrate detoxifying effects obviously are better than the bis-phenol amino acid, show that the introducing of benzyl position chelation group carboxyl can obviously improve detoxifying effect.And compound 6 gained sodium salt detoxifying effects are suitable with compound 6, part of compounds determination of activity result such as table 1.Further measurement result to the rat decorporation effect of acute uranium poisoning shows (table 2), compare with the blank group, compound 5 and 6 all has obvious row's uranium effect (P＜0.05), and wherein the urine uranium output of compound 6 is apparently higher than compound 5 and bis-phenol amino acid.And because the introducing of benzyl position carboxyl, single substitution compound 5 can reach detoxifcation and the decorporation effect suitable with the bis-phenol amino acid.
The detoxifying effect (n=10) that table 1. compound is poisoned to the mouse different metal
Figure BSA00000818574800051
Figure BSA00000818574800061
The impact that table 2 compound is drained rat urine uranium
Figure BSA00000818574800062
N=10)
Figure BSA00000818574800063
* P＜0.05 is compared with the blank group.

Claims (7)

  1. General formula (I) and (II) shown in amino substituted carboxylic acid compounds or its pharmacy acceptable salt class,
    Figure FSA00000818574700011
    Wherein:
    R 1Be hydrogen, CH 2CO 2H;
    R 2Be hydrogen, halogen, nitro, sulfonic group, carboxyl, C1～C6 alkoxyl group;
  2. 2. according to claim 1 described amino substituted carboxylic acid compounds or its pharmacy acceptable salt class is characterized in that: compound general formula (I) and (II) in CO 2H and R 1Middle CO 2H salify CO 2R 3), described salt R 3Positively charged ion is alkali metal cation, alkaline earth metal cation, ammonium cation or basic aminoacids (such as arginine, Methionin or Histidine).
  3. 3. the synthetic method of the described compound of claim 1 is characterized in that: replace o-phenol and different mol ratio 2-oxo acetic acid, 2-Padil or iminodiethanoic acid at water, ethanol, ethanol/H 2O, H 2O/ acetic acid, or ethanol/H 2O/ acetic acid do to react under the solvent general formula (I) and (II) shown in compound.
  4. 4. the synthetic method of the described compound pharmacy acceptable salt of claim 2, it is characterized in that: general formula (I) and (II) described compound and mineral alkali, organic bases or basic aminoacids salt-forming reaction at solvent methanol, ethanol, ether, tetrahydrofuran (THF), acetone, water, 1, carry out in the mixed solvent of 4-dioxane, DMF or above-mentioned solvent.
  5. 5. pharmaceutical composition, its contain the general formula described in claim 1 or 2 (I) and (II) shown in compound or its pharmacy acceptable salt class, and one or more pharmaceutical carriers or vehicle.
  6. General formula described in the claim 1 or 2 (I) and (II) shown in compound or its pharmacy acceptable salt class purposes aspect preparation metal poisoning control and metal decorporation medicine and healthcare products.
  7. 7. purposes as claimed in claim 6 is characterized in that poisoning control and decorporation to the preferred Mn of described metal, Mg, Sr, Fe, Ba, Ni, U, especially U.
CN201210520344.6A 2012-12-06 2012-12-06 Preparation and application of amino substituted carboxylic acid compounds Expired - Fee Related CN102942497B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111574406A (en) * 2020-05-28 2020-08-25 陕西科技大学 Polycarboxyl chelating agent, and preparation method and application thereof

Citations (4)

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Publication number Priority date Publication date Assignee Title
JPS6445348A (en) * 1987-08-13 1989-02-17 Sagami Chem Res Production of n-substituted-l-amino acid derivative
US5122461A (en) * 1990-11-19 1992-06-16 Industrial Technology Research Institute Preparation of pyrocatecholic compounds
CN101898957A (en) * 2009-05-27 2010-12-01 中国石油天然气股份有限公司 Method for synthesizing 3, 4-dihydroxyl mandelic acid by glyoxylic acid method
CN102727473A (en) * 2011-04-08 2012-10-17 复旦大学 Pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine and derivatives thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6445348A (en) * 1987-08-13 1989-02-17 Sagami Chem Res Production of n-substituted-l-amino acid derivative
US5122461A (en) * 1990-11-19 1992-06-16 Industrial Technology Research Institute Preparation of pyrocatecholic compounds
CN101898957A (en) * 2009-05-27 2010-12-01 中国石油天然气股份有限公司 Method for synthesizing 3, 4-dihydroxyl mandelic acid by glyoxylic acid method
CN102727473A (en) * 2011-04-08 2012-10-17 复旦大学 Pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine and derivatives thereof

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Title
陈文致等: "铀促排药物研究：两种新型膦酸类螯合剂的合成", 《药学学报》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111574406A (en) * 2020-05-28 2020-08-25 陕西科技大学 Polycarboxyl chelating agent, and preparation method and application thereof

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