Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-12-28
2001-10-23
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S009100, C514S053000, C514S836000, C530S322000, C536S004100, C536S017200, C536S017500, C536S017600, C536S018500
Reexamination Certificate
active
06306837
ABSTRACT:
The present invention relates to a heavy metal chelating agent, in particular a new kind of oral heavy metal chelating agents comprising glucose as kinetophore and cysteine as pharmacophore, the preparation process and uses thereof.
Heavy metals, typically lead, are harmful to human body. Human beings are always affected in various ways by a variety of heavy metal pollution in daily life. For example, lead pollution exists in almost all the vivosphere of human beings, including atmospheric pollution, potable water pollution and soil pollution. Such pollution sources are introduced into human body while people take in food, inhale air, drink water and smoke, and are assimilated, then dispersed and stored in important organs, resulting in disturbing normal metabolism and poisoning. Ninety percent of lead introduced into human body disperses in the bones. The half-life period of lead in vivo is about 1460 days. Recent research indicates that intracellular lead binds to organelle and protein. The binding is observed namely at mercapto group (—SH) of protein. The amount of the accumulated lead in vivo is increasing with age. Chronic accumulation of lead in vivo leads to changes in normal physiological function of human body.
While acute lead-poisoning population mainly spreads in industrial regions where lead vapor and smoke dust are discharged, waste gas containing lead from motors affects residents in cities by chronic lead poisoning. While children casually suffer from lead poisoning due to unwittingly taking in the peeling-off paint (from toys, furniture, wall and soil, etc.) Containing lead, porcelain tableware containing lead makes anyone suffer from chronic lead poisoning.
Main symptoms of lead poisoning include anepitihyimia, insonmia, headache, dizziness, muscle and joint ache, abdominalgia, astriction, belch and metal smelling in mouth. Lead is fatally toxic to nervous system. Lead poisoning causes disturbance of cerebral cortex excitement and inhibition, malfunction of cortex-internal organs regulation, neurasthenic symptom grouping, and toxic multiple neuritis as well as toxic brain diseases.
Drugs, which are clinically administered at present, are classified into two types, amino-carboxyl compounds and mercapto compounds. The amino-carboxyl compounds include calcium disodium edetate (CaNa
2
-EDTA), calcium trisodium dietlhylenetriaminepentaacetate (CaNa
3
-DTPA). The mercapto compounds include penicillamine and sodium dimercaptosuccinate. These drugs can neither be orally administered nor enter the intracellular sites. What's more, they have the drawbacks of poor selectivity and high toxicity and side effects. Therefore, their applications are rigidly restricted. It is of practical significance to seek to develop a kind of heavy metal antidote which is suitable for oral administration, has less toxicity and side-effects, and is assimilated easily as well.
An object of the present invention is to provide a new kind of oral heavy metal chelating agents comprising glucose as kinetophore and cysteine as pharmacophore.
Another object of the present invention is to provide a preparation process of the said new oral heavy metal chelating agents.
A further object of the present invention is to provide the uses of the said heavy metal chelating agents.
The new oral heavy metal chelating agents of the present invention are chemically defined as &agr;-[D(+)glucosc-1-yl-anmino]-&mgr;-mercapto-(S)-propanoic acid (thereinafter referred to in its al)l)reviated form as NGP,I) and/or N,N′-di[D(+)glucose-1-yl]-L-cystine (thereinafter referred to in its abbreviated form as NGCD,II), their structural formnulae are respectively as follows:
The compounds of formulae (I) and (II) are tested on animals. The result demonstrates that the compounds of the present invention significantly reduce lead content accumulated in organs and bones of mice after they are orally administered. During the period of treatment with the compounds of the present invention, lead content in feces and urine of animals increases remarkably. Therefore, the compounds of the present invention have significant abilities to accelerate the excretion of lead.
The compounds of the present invention show no effect on the concentration of iron, copper, zinc, manganese and calcium in mouse kidneys compared with control groups therefor, the compounds of the present invention can selectively excrete lead in kidney.
After the compounds of the present invention are orally administered to Kunming mice once, with a dose up to 3.0 g/kg body weight, no animal dies. Therefore, the compounds of the present invention are hypotoxic.
The compounds of the present invention show the same remarkable treatment effect in the experiments of accelerating the excretion of cadmium.
The preparation process of the new oral heavy metal chelating agent NGP,I of the present invention comprises reacting glucose and cysteine with a base, with a reducing agent, and followed by acidification to give NGP,I.
The new oral heavy metal chelating agent NGP,I of the present invention may further react with an organic base to give NGCD,II; said organic base may be N-methyl morpholine, the reaction temperature is 20-40° C., and the reaction time is 22-26 hours.
Said cysteine is one of the essential amino acids for human body. The unique mercapto group of the cysteine has a strong affinity for heavy metals. The said glucose has an ability of active transmembrane transportation. Therefore, the compounds of formulae (I) and (II) comprising glucose as kinetophore and cysteine as pharmacophore according to the present invention can accelerate the excretion of heavy metals.
In the reaction of glucose and cysteine with a base, the base can be an organic base or an inorganic base, including sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and trimethylamine; the solvent includes methanol, water, and the reaction is conducted under the protection of nitrogen at 40-90° C. for 10-30 hours. The further reaction with a reducing agent is conducted with stirring at 30-60° C. for 3-5 days, wherein the reducing agent includes sodium borohydride, potassium borohydride and lithium aluminum hydride. And, in the subsequent acidification step, the acid can be a concentrated chlorhydric acid, phosphoric acid and acetic acid and pH is adjusted to 1-2.
The following is the specific synthetic scheme of the above reactions:
The structural feature of the compounds of the present invention is that they contain glucose and cysteine in their molecules. Compared with the heavy metal-excreting drugs of prior art, the compounds of the present invention have four advantages, that is, they are suitable for oral administration, and have high excreting ability, high selectivity and less toxicity.
The new compounds of the present invention can be used in and/or as drugs orally administered to excrete heavy metals, health foods and food additives; the compounds of the present invention can also be used in and/or as drugs orally administered to excrete lead, health foods and food additives; the compounds of the present invention can also be used in and/or as drugs orally administered to excrete cadmium, hydrargyrum, aluminum, stibonium and arsenic, health foods and food additives.
REFERENCES:
patent: 5668272 (1997-09-01), Prasad et al.
patent: 5705585 (1998-01-01), Hogan, Jr.
patent: 5981467 (1999-11-01), Hogan, Jr.
patent: 5994517 (1999-11-01), Tso et al.
Li Xingwei
Mo Taigang
Peng Shiqi
Wang Chao
Wu Yancheng
Jenkens & Gilchrist a Professional Corporation
Sichuan Research Institute of Nature Drugs
Wilson James O.
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