CN101450056B - New use of sodium ion channel blocker in treating biology drug resistance of antibiotic - Google Patents
New use of sodium ion channel blocker in treating biology drug resistance of antibiotic Download PDFInfo
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- CN101450056B CN101450056B CN 200710195690 CN200710195690A CN101450056B CN 101450056 B CN101450056 B CN 101450056B CN 200710195690 CN200710195690 CN 200710195690 CN 200710195690 A CN200710195690 A CN 200710195690A CN 101450056 B CN101450056 B CN 101450056B
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- antibiotic
- fugu ocellatus
- ocellatus toxin
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- ion channel
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Abstract
The invention relates to the application field for treating medicament resistance of antibiotic series medicaments for human body or biology of sodium ion channel regulating agent series compounds and medical salts and esters, especially relates to new application for treating medicament resistance of antibiotic series medicaments for human body or biology of the compounds, According to the sodium ion channel regulating agent series compounds and medical salts and esters of the invention, the medicament resistance for human body or biology generated by the antibiotic series medicaments can be effectively treated, thereby improving the sensitivity rate and the potency of the antibiotic series medicaments for various viruses.
Description
Technical field
The present invention relates to sodium ion channel antagonist compound and pharmaceutical salts thereof and ester in the application for the treatment of antibiotic to human body or biology drug resistance
Background technology
Sodium ion channel antagonist compound of the present invention and medicinal salt or ester thereof refer to 1, the amino perhydrogenate quinazoline ditosylate salt micromolecule chemical constituent of the natural aquatic biological extraction take Fugu ocellatus toxin (tetrodotoxin) as representative or synthetic.Its molecular structural formula:
Fugu ocellatus toxin planar structure (I) Fugu ocellatus toxin stereochemical structure (II)
In the formula: R
1=R
2=R
4=R
5=OH, R
3=CH
2OH; Fugu ocellatus toxin (tetrodotoxin)
R
1＝R
3＝R
4＝R
5＝OH，R
2＝CH
2OH；
Fugu ocellatus toxin molecular formula: C
11H
17N
3O
8, molecular weight 319.27.
2, the diguanidino-prine-hydride compounds from natural aquatic biological extraction or synthetic take saxitoxin (saxitoxin) as representative.Its molecular structural formula:
R
1=R
2=R
3=R
4=H saxitoxin (STX)
R
1=OH, R
2=R
3=R
4=H N-STX (N-STX)
R
1=OH, R
2=R
4=H, R
3=OSO3 POP (POP)
Fugu ocellatus toxin (Tetrodotoxin, be called for short TTX) compounds and Saxidomus (saxitoxin, abbreviation STX) compounds is to extract to separate and synthetic from aquatic organism the earliest, about extracting and synthetic early has bibliographical information, Fugu ocellatus toxin and Saxidomus table 2 application of sample recovery test result
07101439995 and document
[1]The biological activity of the Na-ion channel blocker of indication is extremely strong among the present invention, in the existing technology, yet there are no about indication among the present invention, the salt of amino perhydrogenate quinazoline compounds and diguanidino-prine-hydride compounds and derivant thereof and ester are used for the treatment of antibiotic to the applied research of human body or biology drug resistance.
Antibiotic is that the mankind overcome disease, guarantees health, and life lengthening must indispensable medicine.Be used for clinical from nineteen twenty-eight Britain microbiologist Fei Laiming discovery of penicillin (penicillin Penicillin) to nineteen forty-two penicillin production in enormous quantities, so far there be more than 60 year, in the meantime, the whole world has at least 5,000,000,000 people to benefit from various types of antibiotic medicines.In decades, the people who brings back to life with antibiotic is countless.Antibiotic comprises that antibacterial, fungus, spirillum, actinomycetes, mycoplasma, chlamydia have inhibition and killing action, and cancerous cell and malignant tumor is also had good inhibition and killing action not only to the pathogenic microorganism.
The antibiotic medicine that uses clinically at present has more than 500 kind approximately, and these antibiotic have just become the most frequently used class medicine of clinical departments doctor.Can say that the mankind can have good health and a long life and the high-quality life of today, the antibiont quasi drugs is to perform meritorious deeds never to be obliterated.Yet human also having caused in a large amount of various diseases of using the microorganism of antibiotic therapy pathogenic to import to the mankind depended on unduly and abused antibiotic, and this result will cause the pathogenic microorganism that the antibiotic of its antagonism is produced " drug resistance ".According to antibiotics of scientific statistics human development, almost to spend time and the billions of U.S. dollar of 10-20, but because undue dependency and unconscious abuse that human simple pursuit antibiotic fast treating effect and people produce antibiotic, an antibiotic newly developed often just makes the sex pheromone in the human body that it has been produced Antagonism in 1-2.Make antibiotic lose the value for the treatment of human major disease.Some patient is because too much abuse of antibiotics almost will reach the stage of the disease that pasts medical help.In addition, human the phenomenon of abuse of antibiotics is also very general in agriculture and animal husbandry plantation aquaculture, culture fishery, and almost whole antibiotic of mankind itself's use all are widely used in farming and animal husbandry, culture fishery.Scientific research confirms that drug-resistant bacteria can pass to another area from an area, passes to another country from a country, even passes to the people from animal, plant.Make human body ignorant or unconscious in " the drug resistance pathogenic bacteria " or " the Residual Disease bacterial strain of sex pheromone " of putting aside in passive, plant mode by food chain infect.Along with people exchange frequent and convenient, drug-resistant bacteria propagates in the human body and to produce the antibiotic speed of antagonism more and more faster, scope is more and more wider.So antibiotic resistance has become global serious problems.Scientific discovery, the nature sex pheromone is ubiquitous, and itself also is a life, can defend oneself, defend, strikes back when the material that the outside is arranged is invaded, and last result is exactly drug resistance.It is the inevitable measure of pathogenic microorganism protection oneself.The survival strategy of pathogenic microorganism, to conform by every possible means, just begin amount reproduction in the human body cell once enter, then break out and infect other cells, stop its constantly to make and procreation, people only know at present is exactly to use various antibiotic, can effectively kill these pathogenic microorganisms.Yet because the life cycle of pathogenic microorganism is very short, the interval of Dai Yudai is very little.Almost equaled a generation in 4 hours, each can breed more than 1,000 times from generation to generation, over time and constantly multiplication, once human body is ill by the little property of source of disease biological infection, even patient uses the antibiotic that can kill this pathogenic microorganism, in the middle of as long as a pathogenic microorganism producer sudden change of also not being killed by antibiotic or killing and wounding is arranged, produce paraprotein, this paraprotein can cause drug-fast strain and generate.The mankind will solve this pathogenic microorganism antibiotic is produced the gene evolution that this pathogenic microorganism just must be controlled and prevent to chemical sproof emphasis.
Purpose of the present invention is studied exactly and is found that Na-ion channel blocker is can establishment " drug resistance pathogenic bacteria " or the chemical constituent of " the Residual Disease bacterial strain of sex pheromone ", use medicine or the chemical constituent of Na-ion channel blocker class of the present invention, can be fast excrete human body or in vitro with " drug resistance pathogenic bacteria " residual in the human body or in the animal body or " the Residual Disease bacterial strain of sex pheromone " antagonism or with it, reduce the pathogenic microorganism to Antibiotic resistance.
Summary of the invention
One of purpose of the present invention is to use sodium ion channel antagonist compound and officinal salt or ester, and preparation treatment antibiotics medicine produces chemical sproof application to human body or organism.
Two of purpose of the present invention be when using sodium ion channel antagonist compound to significantly improve the antibiotic drug effect, and the Na-ion channel blocker self that uses can not remain in human body or the organism.
Another object of the present invention is the using dosage that uses residual drug resistance sex pheromone in sodium ion channel antagonist compound treatment human body or the organism.
The Na-ion channel blocker that the present invention uses refers to, one, amino perhydrogenate quinazoline compounds is for the chemical compound of representative and derivant or synthetic (modification) chemical constituent and pharmaceutical salts and ester with Fugu ocellatus toxin (tetrodotoxin is called for short TTX); Two, diguanidino-prine-hydride compounds is for the chemical compound of representative and derivant or synthetic (modification) chemical constituent and pharmaceutical salts and ester with saxitoxin (saxitoxin is called for short STX).Amino perhydrogenate quinazoline compounds described in the present invention and derivant thereof or synthetic (modification) chemical constituent and pharmaceutical salts thereof and esterification structural formula are as follows:
Fugu ocellatus toxin planar structure (I) Fugu ocellatus toxin stereochemical structure (II)
In the formula: R
1=R
2=R
4=R
5=OH, R
3=CH
2OH; Fugu ocellatus toxin (tetrodotoxin)
R
1=R
3=R
4=R
5=OH, R
2=CH
2OH; Different Fugu ocellatus toxin
The Fugu ocellatus toxin molecular formula is: C
11H
17N
3O
8, molecular weight 319.27, patent CN2007101439995 is seen in the research of its chemical structural formula.
The present invention prepares the technical characterictic of amino perhydrogenate quinazoline derivative and pharmaceutically acceptable salt or ester composition, is natural extract take Fugu ocellatus toxin as precursor structure or the chemical compound of synthetic, wherein:
R
1Be selected from: hydrogen; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
3=R
4=R
5=OH, R
2=CH
2OH.
Work as R
1=H, or during OH, R
2Be selected from: CH
2OH; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; C
1-C
6The alkanal base; R
3=R
4=R
5=OH.
Work as R
1=H, or OH; R
2=CH
2During OH, R
3Be selected from: hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
4=R
5=OH.
Work as R
1=H, or during OH, R
2=CH
2OH; R
3During=OH; R
4Be selected from hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
5=OH.
Work as R
1=H, or during OH, R
2=CH
2OH; R
3=R
4=OH; R
5Be selected from: hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl;
The Main Derivatives and the pharmaceutically acceptable salt thereof that can be used for implementing the preferred Fugu ocellatus toxin of new purposes of compositions of the present invention have:
R
1=H, R
3=R
4=R
5=OH, R
2=CH
2OH; (deoxidation Fugu ocellatus toxin)
R
1=OCH
3, R
3=R
4=R
5=OH; R
2=CH
2OH; (methoxy Fugu ocellatus toxin)
R
1=OCH
2CH
3, R
3=R
4=R
5OH; R
2=CH
2OH; (ethoxy Fugu ocellatus toxin)
R
1=NH
2, R
3=R
4=R
5OH; R
2=CH
2OH; (amino Fugu ocellatus toxin)
The present invention prepares the Fugu ocellatus toxin (I) of compositions technical characterictic in weakly acidic aqueous solution or saline solution, is that tautomer or the enantiomeric form with ester and hemiacetal group exists (II),
In the formula:
R
1=R
3=R
4=R
5=OH, R
2=CH
2OH; Carbon 7-ester group or hemiacetal group isomer
R
1=R
2=R
4=R
5=OH, R
3=CH
2OH; Different carbon 7-ester group or hemiacetal group isomer
In the formula: R
1=R
2=R
4=R
5=OH, R
3=CH
2OH; Different carbon 5-ester group or hemiacetal group isomer
R
1=R
3=R
4=R
5=OH, R
2=CH
2OH; Carbon 5-ester group or hemiacetal group isomer
The new purposes of the present composition, the Fugu ocellatus toxin of technical characterictic (I) easily are converted into C-4 tautomer or enantiomer (III) under faintly acid and saline solution condition,
In the formula:
R
1=R
3=R
4=R
5=OH, R
2=CH
2OH; 4-shows Fugu ocellatus toxin
R
1=R
2=R
4=R
5=OH, R
3=CH
2OH; Different 4-table Fugu ocellatus toxin
A class natural extract or artificial-synthetic compound and pharmaceutically acceptable salt thereof take C-4 table Fugu ocellatus toxin as representative, wherein:
R
1Be selected from hydrogen; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
3=R
4=R
5=OH, R
2=CH
2OH.
Work as R
1=H, or during OH, R
2Be selected from: CH
2OH; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; C
1-C
6The alkanal base, R
3=R
4=R
5=OH.
Work as R
1=H, or OH; R
2=CH
2During OH, R
3Be selected from: hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
4=R
5=OH.
Work as R
1=H, or during OH, R
2=CH
2OH; R
3During=OH; R
4Be selected from hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
5=OH.
Work as R
1=H, or during OH, R
2=CH
2OH; R
3During=OH; R
4=OH; R
5Be selected from: hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl;
The Fugu ocellatus toxin (I) of the new purposes technical characterictic of the present composition under acidity and the saline solution condition, easily becomes dehydration (dehydroxylation) Fugu ocellatus toxin (IV) and their enantiomer in room temperature,
In the formula: R
2=R
4=R
5=OH, R
3=CH
2OH; R
1=H carbon 4-different the Fugu ocellatus toxin that dewaters
R
3=R
4=R
5=OH, R
2=CH
2OH; R
1=H carbon 4-Anh-TTX 4,9-Anhydrotetrodotoxin
R
1=R
4=R
5=OH, R
3=CH
2OH; R
2The different Anh-TTX 4,9-Anhydrotetrodotoxin of=H carbon 6-
R
1=R
4=R
5=OH, R
2=CH
2OH; R
3=H carbon 6-Anh-TTX 4,9-Anhydrotetrodotoxin
R
1=R
2=R
5=OH, R
3=CH
2OH; R
4The different Anh-TTX 4,9-Anhydrotetrodotoxin of=H carbon 8-
R
1=R
3=R
5=OH, R
2=CH
2OH; R
4=H carbon 8-Anh-TTX 4,9-Anhydrotetrodotoxin
R
1=R
2=R
4=OH, R
3=CH
2OH; R
5The different Anh-TTX 4,9-Anhydrotetrodotoxin of=H carbon 9-
R
1=R
3=R
4=OH, R
2=CH
2OH; R
5=H carbon 9-Anh-TTX 4,9-Anhydrotetrodotoxin
The Fugu ocellatus toxin of the new purposes of the present composition (I) under highly acid and the saline solution condition, (I) easily becomes two dehydration (dehydroxylation) Fugu ocellatus toxin ethers (V or VI or VII) or their enantiomer in room temperature,
In the formula: R
2=R
4=R
5=OH, R
3=O=R
1Carbon 4, carbon 11-are dehydrated into different Fugu ocellatus toxin ether
R
3=R
4=R
5=OH, R
2=CH
2O=R
1Carbon 4, carbon 11-is dehydrated into Fugu ocellatus toxin ether
In the formula: R
3=R
5=OH, R
2=CH
2OH R
4=O=R
1Carbon 4, carbon 8-is dehydrated into Fugu ocellatus toxin ether
In the formula: R
3=R
4=OH, R
2=CH
2OH, R
5=O=R
1Carbon 4, carbon 9-is dehydrated into Fugu ocellatus toxin ether
Preferred 4 in the formula, 9-Anh-TTX 4,9-Anhydrotetrodotoxin, 4,9 dehydration 6-table Fugu ocellatus toxin
In room temperature, under the strong alkaline condition, (I) be transformed into easily Fugu ocellatus toxin acid (VIII) analog derivative and ester thereof,
In the formula:
R
1=R
3=R
4=R
5=OH, R
2=CH
2OH; The R=H tetrodonic acid
R
1=R
2=R
4=R
5=OH, R
3=CH
2OH; The different tetrodonic acid of R=H
Natural extract take the Fugu ocellatus toxin acids as representative or artificial-synthetic compound, wherein:
R
1Be selected from hydrogen; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
2=R
4=R
5=OH, R
3=CH
2OH; R=C
1-C
8Alkyl or aromatic ring.
Work as R
1=H, or during OH, R
2Be selected from: CH
2OH; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; C
1-C
6The alkanal base; R
3=R
4=R
5=OH, R=C
1-C
8Alkyl, alkylamino, C
1-C
5The alkane hydroxyl; Halogen or aromatic ring.
Work as R
1=H, or OH; R
2=CH
2During OH, R
3Be selected from: hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
4=R
5=OH; R=C
1-C
8Alkyl, alkylamino, C
1-C
5The alkane hydroxyl; Halogen or aromatic ring.
Work as R
1=H, or during OH, R
2=CH
2OH; R
3During=OH; R
4Be selected from hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
5=OH; R=C
1-C
8Alkyl, alkylamino, C
1-C
5The alkane hydroxyl; Halogen or aromatic ring.
Work as R
1=H, or during OH, R
2=CH
2OH; R
3During=OH; R
4=OH; R
5Be selected from: hydrogen; Hydroxyl; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R=C
1-C
8Alkyl, alkylamino, C
1-C
5The alkane hydroxyl; Halogen or aromatic ring.
Work as R
1=R
3=R
4=R
5=H, or during OH, R
2=CH
2OH, R is selected from; C
1-C
5The alkane hydroxyl; Halogen; C
1-C
5Alkoxyl; C
1-C
5Halogenated alkoxy; C
3-C
6Cycloalkyloxy; C
3-C
6Cycloalkyl; C
2-C
6Alkenyl; C
2-C
6Alkynyl group; C
5-C
10Aryl moiety and C
1-C
6The aralkyl of moieties or C
5-C
10Aryl; Amino; C
1-C
6Alkylamino; Acyl group; C
1-C
6Alkanoyl; R
5=OH; R=C
1-C
8Alkyl, alkylamino, C
1-C
5The alkane hydroxyl; Halogen or aromatic ring.
Wherein preferred tetrodonic acid and ester thereof have:
R
1=R
3=R
4=R
5=OH, R
2=CH
2OH; R=C
1-C
8Alkyl or aromatic ring, the Fugu ocellatus acid esters
R
1=H, R
2=R
4=R
5=OH, R
3=CH
2OH; R=C
1-C
8Alkyl or aromatic ring, deoxidation Fugu ocellatus acid esters
R
1=OCH
3, R
2=R
4=R
5OH; R
3=CH
2OH; R=C
1-C
8Alkyl or aromatic ring, methoxy Fugu ocellatus acid esters
R
1=OCH
2CH
3, R
2=R
4=R
5OH; R
3=CH
2OH, R=C
1-C
8Alkyl or aromatic ring, ethoxy Fugu ocellatus acid esters
R
1=NH
2, R
2=R
4=R
5OH; R
3=CH
2OH; R=C
1-C
8The amino Fugu ocellatus acid esters of alkyl or aromatic ring
Diguanidino-prine-hydride compounds described in the present invention and pharmaceutical salts thereof and ester are take saxitoxin as main chemical compound and derivant or synthetic (modification) chemical constituent.Its chemical structural formula is
[4]:
R
1=R
2=R
3=R
4=H saxitoxin (STX)
R
1=OH, R
2=R
3=R
4=H N-STX (N-STX)
R
1=OH, R
2=R
4=H R
3=OSO
3POP (POP)
Na-ion channel blocker can be single-minded the prevention sodium ion enter in the cell, stop neurocyte, muscle cell to produce excitation activity.Scientific research thinks that cell membrane has different permeabilitys to different material.The ion concentration difference that film is inside and outside is mainly potassium ion in the film, film is mainly sodium ion outward.The outside keeps the negative resting potential of 50-100mv usually in the cell membrane.Neural an excitatory potential is poor just changes, and namely produces depolarization.This potential change has increased the permeability of sodium ion cell membrane, and sodium ion is first-class to be entered in the neural cell membrane, and transmembrane potential just changes, and potassium ion flows out with that.A series of like this variation makes between the part adjacent with the film surface and has caused minor loop, and the minor loop that causes causes the adjacent regions depolarization, because depolarization causes cell membrane excited again, increases sodium ion inflow, this kind form is transmitted one by one to contiguous position.The speed of transmitting is the 0.1-100 meter per second.Excited in a single day disappearance, the sodium ion of inflow is got back to again the cell membrane outside, and potassium ion flows into the inboard of film, produces depolarization.This also is the communication channel of cell membrane, and Fugu ocellatus toxin and saxitoxin and derivant thereof or its salt, ester are that the current potential extreme difference of control cell membrane changes, and stop the circulation of sodium ion, and its information relevant with sodium is obstructed.After sodium-ion channel was blocked in body, the nervous system of body, cardiovascular system, metabolic function all can produce significant variations.We also fail clear elaboration at present but how Na-ion channel blocker of the present invention and acceptable salt thereof or esters get rid of the antibiotics resistance bacterial strain external mechanism in vivo, still continuing research, but this does not limit practical use of the present invention and result of use thereof.
The amino perhydrogenate quinazoline compounds of the present invention's preparation and diguanidino-prine-hydride compounds and derivant and its pharmaceutically acceptable salt, comprise the mineral acid example hydrochloric acid, hydrobromic acid, hydroiodic acid, hypochlorous acid, sulphuric acid, sulfurous acid, thiosulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, carbonic acid, inferior carbonic acid, nitric acid, nitrous acid and acylate, comprise acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, hemisuccinic acid, salicylic acid, methanesulfonic acid, alkyl benzene sulphonate, salt or esters that hippuric acid etc. form, can be according to the carrier on the existing pharmaceutical technology use materia medica, excipient or other additives, make various dosage forms, as be made into subcutaneous, muscle, acupuncture point or intravenous injection, oral formulations (comprising sublingual lozenge), oil formulation, skin sticks, infiltration, the pump infiltration, supp anal, aerosol.Optimizing injection, oral formulations and skin patch.Preparation contains Fugu ocellatus toxin and saxitoxin purity is 80--110%, most preferably is 90-105%.Its preparation contains Fugu ocellatus toxin and diguanidino-prine-hydride compounds and is the 80-120% of labelled amount.Most preferably be 90-110%.Use amino perhydrogenate quinazoline compounds and diguanidino-prine-hydride compounds and dosage be: per unit human body or organism medication are: everyone or every biological 0.001--50 μ g/ time, 1-2 times/day.Most preferably be 0.01--30 μ g/ time.
Amino perhydrogenate quinazoline compounds described in the present invention and diguanidino-prine-hydride compounds reach at the treatment antibiotic people or the chemical sproof new purposes of organism, the antibiotic of indication produces the drug resistance virus strains, be by at present common and commonly use clinically various antibiotic caused or caused.As: (1) amine antibiotic mainly comprises two large classes: 1. penicillins also is beta-lactam the earliest, its medicine commonly used has penicillin sodium salt or potassium salt, ampicillin, piperacillin, amoxicillin, procaine benzylpenicillin, oxacillin sodium, cloxacillin sodium, piperacillin, the azlocillin, mezlocillin, ticarcillin sodium, mecillinam, penicillin V etc., 2. cephalosporins, medicine commonly used has cefalexin, cefadroxil, Ancef number, cefradine, ceftriaxone, ceftriaxone sodium, cephalothin sodium, cefathiamidine, cefazolin sodium, cefatrizine, cefaclor, cefamandole, cefuroxime, CEFUROXIME AXETIL, cephalo is for ammonia, cefotaxime, ceftizoxime, cefmenoxime, cefoperazone, ceftazidime, the pyridine of cephalo ground, cefuzonam, Cefpodoxime Proxetil, cefixime, cefdinir, cefteram, cefpirome, cephalo Bush, cephalo draws nurse ester, cefotetan, cefminox, cefmetazole, latamoxef, cefepime, cefprozil etc., (2) aminoglycoside (glycoside) class, medicine commonly used has streptomycin, neomycin, amikacin, tobramycin, sisomicin, netilmicin, etimicin, nuclear is for Mi Xing, ground shellfish rice star, isepamicin, micronomicin, spectinomycin, gentamycin, kanamycin, micronomicin, astromicin etc., (3) Tetracyclines, medicine commonly used has tetracycline, oxytetracycline, doxycycline, chlortetracycline, minocycline etc., (4) chloromycetin, medicine commonly used has chloromycetin, chloramphenicol palmitate, thiamphenicol etc., (5) Macrolide, medicine commonly used has erythromycin, Roxithromycin, rokitamycin, dirithromycin, erythromycin ethylsuccinate, midecamycin, Acetylmidecamycin, acetylspiramycin, kitasamycin, clarithromycin, azithromycin, meleumycin etc., (6) lincomycin class, medicine commonly used has lincomycin, clindamycin, lincomycin etc., (7), the antibacterium antibiotics, medicine commonly used has norvancomycin, fosfomycin, polymyxin, capreomycin, rifampicin, bacitracin, fusidic acid, teicoplanin etc., (8), the antifungal antibiotic class, medicine commonly used has amphotericin B, griseofulvin, cannitracin, nystatin, hachimycin, Caspofungin, flucytosine, miconazole, fluconazol, itraconazole, terbinafine, clotrimazole, econazole, Fu Lakang azoles, tioconazole etc., (9), the antitumor antibiotics class, medicine commonly used has mitomycin, amycin, epirubicin, actinomycin D, bleomycin, Bleomycin A5, peplomycin, daunorubicin etc., (10) have the antibiotics of immunosuppressive action, and medicine commonly used has ciclosporin, aciclovir, Ah bran's adenosine, idoxuridine, ribavirin, ganciclovir, lamivudine etc., (11), quinolones, medicine commonly used has ofloxacin, ciprofloxacin, norfloxacin, enoxacin, pefloxacin, tosufloxacin, fleroxacin, lomefloxacin, rufloxacin, Gatifloxacin, moxifloxacin, sparfloxacin, levofloxacin magnitude, (12), the tuberculosis class, kind commonly used has isoniazid, ftivazide, pyrazinamide etc., (13), antibiotic and enzyme inhibitor combination medicine class, kind commonly used has amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/Tazobactam Sodium, ticarcillin/clavulanate potassium, Sulbactam/Cefoperazone, imipenum/betamipron, and the drug resistance pathogenic bacteria strain residue that people or organism are produced such as meropenem.
Present scientific research thinks that sex pheromone produces drug resistance mechanism to antibiotic, and following reason is arranged:
1, sex pheromone produces the drug inactivation enzyme, such as beta lactamase beta-lactam class antibiotic is lost efficacy; Such as the aminoglycoside modification enzyme aminoglycoside was lost efficacy; Present most important beta lactamase is three kinds of extended spectrum β lactamases (Extended spectrumbeta-lactamases, ESBLs), chromosome AmpC (AmpC) and carbapenem hydrolytic enzyme (OXA).ESBLs master can be divided into the types such as TEM, SHV, OXA again by plasmid-mediated; AmpC both can be by Chromosome-encoded, also can be by plasmid-mediated, because the cephalosporin percent hydrolysis is higher than penicillins, so be called again cephalosporinase, reach so far more than 30 the sixth of the twelve Earthly Branches and plant, OXA is a kind of of ESBLs enzyme, claim again metal beta lactamase or carbapenem hydrolytic enzyme, energy deactivation penicillin, cephalosporin and carbapenems (training southern class) antibiotic, even energy inactivator inhibitor comprise clavulanic acid, sulbactam and Tazobactam Sodium.In recent years plasmid-mediated carbapenem hydrolytic enzyme also occurred, made noxious bacteria or virus to a lot of broad ectrum antibiotic generation drug resistances.What be worth emphasizing is the drug resistant gene of the same plasmid portability multiclass antimicrobial drug of a kind of antibacterial, namely simultaneously can produce plurality of enzymes, can produce simultaneously ESBLs and AmpC such as escherichia coli and bacillus canalis capsulatus, is called as superpower wide spectrum enzyme (SSBLs).
2, the sex pheromone target site changes, and changes such as antibacterial PBPs to make the change of beta-lactam drug resistance S12 albumen make the streptomycin drug resistance;
3, sex pheromone etc. is set up the target bypath system, such as the newly-built penicillin-binding protein 2 of antibacterial (PB2), makes the methicillin to the staphylococcus aureus drug resistance;
4, the sex pheromone metabolic pathway changes, and antibiotics can be combined with the necessary Cucumber of bacterial growth, affects its growth and breeding, can utilize the synthetic folic acid of controlling oneself such as anti-sulfonamides antibacterial, and not need exogenous PABA;
5, sex pheromone reduces film (wall) permeability, as bacterial membrane protein degeneration, porin (channel protein or outer membrane protein) lack as or form biomembrane, make imipenum to the pseudomonas aeruginosa drug resistance;
6, the sex pheromone membrane pump effluxes, and present known have 5 families, more than 20 kind of efflux pump are the modal drug resistance reasons such as tetracycline, chloromycetin, quinolione class, also are the main causes that antibacterial produces MDR.
So also some scientist thinks that sex pheromone produces drug resistance, all be by sex pheromone chromosome coding mediation plasmid, be due to DNA or RNA suddenly change, this mediation plasmid is not using antibiotic just to exist in the past, and this is actually pathogenic bacteria and will suddenlys change as a kind of measure (SOS that is called for short sex pheromone replys) of egodefense.When pathogenic bacteria is in extreme adverse circumstance lower time, they can attempt variety of way, with the damage that the is subject to initial step as sudden change.Then, they open some genes---and the generation that the albumen of these gene expressions can accelerate to suddenly change, the generation speed of this class sudden change is than fast 10,000 times of the speed that produces sudden change during the cellular replication.In fact, these cells have stood a kind of rapidly identity transformation.When not meeting with antibiotic, they seldom carry drug resistant gene.But since with the mutual antagonism of antibiotic medicine after, the mediation plasmid become the optimum carrier of catching or propagate drug resistant gene.For example, Escherichia coli (being escherichia coli, Escherichia coli) is by sending SOS, and the persistency DNA damage that ciprofloxacin and other antibiotic are caused is made and being replied.Undergo mutation, begin to stop ciprofloxacin in conjunction with its target---gyrase.And gyrase necessary mediation plasmid when being dna replication dna.If sex pheromone SOS replys sudden change, successfully stop the combination of antibiotic and its target-gyrase, pathogenic bacteria will be mutated into Resistant strain, thereby makes antibiotic lose the extremely activity of source of disease bacterial strain.If antibacterial can not stop antibiotic to be combined with gyrase, the DNA of antibacterial just can not normal replication so, will rupture, and then pathogenic bacteria will be dead.This also is the antibiotic sterilization, the effective procedure of curing the disease.This wherein if antibiotic is combined with the target-gyrase of sex pheromone, is not replied sudden change by sex pheromone SOS and blocks.So sex pheromone just not can with antibiotic antagonism process in, residual lower drug-resistant virus bacterial strain in body.This shows if can find certain composition that can close sex pheromone SOS answering system, just can stop the excessive evolution of these antibacterials, just can prevent the excessive sudden change of these antibacterials, also just can solve the drug resistance that sex pheromone produces antibiotic.
Berkeley branch school Floyd scientist Romsberg of California, USA university in 2002 and Ryan T.Cirz, JodieK.Chin and they find the partner of University of Wisconsin Madison, a kind of LexA albumen can anti-bacteria SOS reply, and ciprofloxacin can cause the shearing of LexA albumen, thereby brings out the super sudden change of SOS in the escherichia coli.In case LexA albumen is sheared, three kinds of archaeal dna polymerases just begin to make sudden change, allow antibacterial produce rapidly drug resistance.The small-molecule drug that rom Si Baige has found a kind of energy and antibiotic to take together, this medicine can stop LexA to be sheared.In the ciprofloxacin test that mice is taken, found that mice does not develop immunity to drugs to ciprofloxacin.
The research worker of Sichuan Province China university life academy of science in 2005 finds that Fructus Vitis viniferae extract has elimination O
157The effect of Drug Resistance of E. coli.These achievements in research are illustrated, and Antibiotic resistance is soluble.
The present invention finds, sodium ion channel antagonist compound one, amino perhydrogenate quinazoline compounds are with salt and the ester of Fugu ocellatus toxin (tetrodotoxin is called for short TTX) for the chemical compound of representative and derivant or synthetic (modification) chemical constituent; Two, diguanidino-prine-hydride compounds is with saxitoxin (saxitoxin, be called for short STX) for the chemical compound of representative and derivant thereof or synthesize salt and the ester of (modification) chemical constituent, can suppress significantly sex pheromone, improve antibiotic tiring, perhaps be efflux or make film (wall) permeability to reduce to allow with membrane pump sex pheromone not produce SOS to reply sudden change relevant.
Present studies have shown that, Fugu ocellatus toxin and derivatives class composition thereof block selectively or block cell membrane excitation time sodium ion to flow into cell membrane inboard, thereby the potential change that suppresses the neuromuscular cell membrane, just suppressed the transmission of a neural impulse of excitation, but potassium ion flowing inside and outside cell membrane is not subjected to the impact of Fugu ocellatus toxin yet.In this process the potential difference of the cell membrane of sex pheromone lose after polarized with body in Normocellular in conjunction with chance, Resistant strain is excluded external in the sex pheromone thereby make.Na-ion channel blocker is a kind of extremely strong film extracellular sodium ion channel blocker, when the potential change of block nerves muscle cell membrane, can promote the generation of LexA albumen in human body or the animal body, and when the sodium ion blocker together uses separately or with antibiotic, just can prevent that by sodium-ion channel in the narrow spectrum blocking-up organism antibiotic from being sheared the LexA albumen in the body, and can narrow spectrum inhibition and the antagonism sex pheromone undergo mutation.This variation is not affected by the mechanism of at present known various drug-resistant virus bacterial strains.Although producing chemical sproof mechanism, antibiotic has a lot, scientist does not also make clear fully at present, being still waiting us further furthers investigate, but our existing experiment, do not affect enforcement of the present invention, the Na-ion channel blocker of the application of the invention can significantly improve antibioticly tires and suppresses endurance strain to the Drug resistance of human body, and perhaps this be that the present invention is to a contribution of human Fighting Disease.
Fugu ocellatus toxin in the Na-ion channel blocker and the pharmacokinetic of saxitoxin confirm that Fugu ocellatus toxin and saxitoxin self can be not residual in body, causes Na-ion channel blocker to the pollution of human body or organism.Employed Fugu ocellatus toxin or saxitoxin be after 48-72 hour when antagonism antibiotics resistance pathogenic bacteria, it self by organism sweat gland, Dung just, the metabolism such as urine excretes.
Na-ion channel blocker of the present invention namely can use separately, also can share with existing various antibiotic.The effect of the antibiotic drug effect that when share with antibiotic, is significantly increased.The antibiosis that share have: (1) amine, mainly comprise: 1. penicillins, 2. cephalosporins, (2) aminoglycoside (glycoside) class, (3) Tetracyclines, (4) chloromycetin, (5) Macrolide, (6) lincomycin class, (7) antibacterium antibiotics, (8) antifungal antibiotic class, (9) antitumor antibiotics class, (10) have the antibiotics of immunosuppressive action, (11) quinolones, (12) tuberculosis class, (13) antibiotic and enzyme inhibitor combination medicine etc.
Remarkable technological progress feature of the present invention is:
1, with the amino perhydrogenate quinazoline of Na-ion channel blocker and the salt of diguanidino-prine-hydride compounds and derivant thereof and the compositions of ester, being used for the treatment of antibiotic is the new purposes that has practical value most that the inventor finds through great many of experiments to people or organism drug resistance, and it can improve human health, quality of life and the prolongation mankind's life expectancy by highly significant the application by present technique.
2, with the salt of sodium ion channel antagonist compound of the present invention and derivant thereof and ester improve antibiotic tire or antibiotic responsive rate be use separately or and other antibiotic formulations share significant result of use all arranged.
When 3, share with sodium ion channel antagonist compound of the present invention and derivative salt thereof and ester and antibiotic, in the antibiotics potentiation that it is share, can also obviously reduce antibiotic side effect.
Also reduced antibiotic using dosage when 4, reducing antibiotic resistance with sodium ion channel antagonist compound of the present invention.
Embodiment
One, the compound method of injection Fugu ocellatus toxin:
1, Fugu ocellatus toxin and salt thereof
A, Fugu ocellatus toxin 5.0 μ g B, Fugu ocellatus toxin 10.0 μ g
Citric acid and sodium salt buffer 2.1: 2.9 μ g salicylic acid and salt 0.15 μ g
Lactose 250.0 μ g lactose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
C, Fugu ocellatus toxin 10.0 μ g D, Fugu ocellatus toxin 15.0 μ g
Tartaric acid and salt 0.15 μ g phosphoric acid and salt 0.15 μ g
Lactose 50.0 μ g sucrose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
2,4-table Fugu ocellatus toxin and salt thereof
E, 4-table Fugu ocellatus toxin 5.0 μ g F, 4-table Fugu ocellatus toxin 10.0 μ g
Citric acid and salt 2.1: 2.9 μ g acetic acid and salt 0.15 μ g
Maltose 25.0 μ g sucrose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
G, 4-table Fugu ocellatus toxin 5.0 μ g H, 4-table Fugu ocellatus toxin 10.0 μ g
Hydrochloric acid and salt 0.14 μ g nitric acid and salt 0.15 μ g
Maltose 25.0 μ g sucrose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
3, Anh-TTX 4,9-Anhydrotetrodotoxin and salt thereof
A, Anh-TTX 4,9-Anhydrotetrodotoxin 5.0 μ g b, Anh-TTX 4,9-Anhydrotetrodotoxin 10.0 μ g
Citric acid and salt 0.14 μ g malic acid 0.15 μ g
Lactose 25.0 μ g lactose 50.0 μ g
Mannitol 7.5mg mannitol 7.5mg
Water for injection 1.0-2.0ml water for injection 0-2.0ml
C, Anh-TTX 4,9-Anhydrotetrodotoxin 5.0 μ g d, Anh-TTX 4,9-Anhydrotetrodotoxin 10.0 μ g
Acetic acid 0.14 μ g tartaric acid 0.15 μ g
Lactose 25.0 μ g lactose 50.0 μ g
Mannitol 7.5mg mannitol 7.5mg
Water for injection 1.0-2.0ml water for injection 0-2.0ml
4, tetrodonic acid and ester thereof
E, Fugu ocellatus toxin acid 10.0 μ g f, Fugu ocellatus toxin acid esters 15.0 μ g
Sodium phosphate 1.5 μ g sodium citrate 0.15 μ g
Sodium citrate 0.01 μ g sucrose 50.0 μ g
Lactose 50.0 μ g mannitol 15.0mg
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
5, amino Fugu ocellatus toxin and ester thereof
G, amino Fugu ocellatus toxin 5.0 μ g h, ethylamino Fugu ocellatus toxin 10.0 μ g
Hydrochloric acid acid 0.14 μ g sulphuric acid 0.15 μ g
Maltose 25.0 μ g sucrose 50.0 μ g
Mannitol 25.0mg mannitol 20.0mg
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
Two, the preparation of Fugu ocellatus toxin salt
Example 1, get Fugu ocellatus toxin (TTX), content (95-99%) 10mg is with citric acid 150 μ g, be modulated into the solution of PH=5.0-7.0 with sodium citrate, contain 10ug by every 2ml and calculate, make 1000 injection, detect with HPLC, after content is qualified, fill, sterilization meets medical sanitary standard or standard for animals, can use, be called for short: Fugu ocellatus toxin salt A.
Example 2, get the deoxidation Fugu ocellatus toxin, content (85-98%) 1mg is with oxalic acid 150 μ g, be modulated into the solution of PH=5.0-7.0 with Disodium oxalate., contain 10ug by every 2ml and calculate, make 1000 injection, detect with PLC, after content is qualified, fill, sterilization meets medical sanitary standard or standard for animals, can use, be called for short: Fugu ocellatus toxin B.
Example 3, get Fugu ocellatus toxin acid, content (85-95%) 1mg is with malic acid 150 μ g, be mixed with the solution of PH=5.0-7.0, contain 10ug by every 2ml and calculate, make 1000 injection, detect with PLC, after content is qualified, fill, sterilization meets medical sanitary standard or standard for animals, can use, be called for short: Fugu ocellatus toxin C.
Example 4, get 4-table Fugu ocellatus toxin, content (95-98%) 1mg is with methanesulfonic acid 150 μ g, be mixed with the solution of PH=5.0-7.0, contain 10ug by every 2ml and calculate, make 1000 injection, detect with PLC, after content is qualified, fill, sterilization meets medical sanitary standard or standard for animals, can use, be called for short: Fugu ocellatus toxin D.
Example 5, get the acid of amino Fugu ocellatus toxin, content (85-95%) 1mg is with tartaric acid 150 μ g, be mixed with the solution of PH=5.0-7.0, contain 10ug by every 2ml and calculate, make 1000 injection, detect with PLC, after content is qualified, fill, sterilization meets medical sanitary standard or standard for animals, can use, be called for short: Fugu ocellatus toxin E.
Three, the compound method of injection saxitoxin:
1, saxitoxin and salt thereof
A, saxitoxin 3.0 μ g B, saxitoxin 10.0 μ g
2.1: 2.9 μ g of citric acid and sodium salcylic acid, 0.15 μ g
Lactose 25.0 μ g lactose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
C, saxitoxin 10.0 μ g D, saxitoxin 5.0 μ g
Tartaric acid 0.15 μ g phosphoric acid 0.15 μ g
Lactose 50.0 μ g sucrose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
2, N-STX and salt thereof
A, N-STX 3.0 μ g B, N-STX 10.0 μ g
Citric acid 1.4 μ g salcylic acids 0.15 μ g
Lactose 25.0 μ g lactose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
C, N-STX 10.0 μ g D, N-STX 5.0 μ g
Tartaric acid 0.15 μ g phosphoric acid 0.15 μ g
Lactose 50.0 μ g sucrose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
3, POP and salt thereof
A, GTX3 .0 μ g B, GTX1 0.0 μ g
Citric acid 1.4 μ g salcylic acids 0.15 μ g
Lactose 25.0 μ g lactose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
C, GTX1 0.0 μ g D, GTX5 .0 μ g
Tartaric acid 0.15 μ g phosphoric acid 0.15 μ g
Lactose 50.0 μ g sucrose 50.0 μ g
Water for injection 1.0-2.0ml water for injection 1.0-2.0ml
Four, the preparation of saxitoxin salt
Example 1, get saxitoxin, content (95-99%) 10mg is with citric acid 150 μ g, be mixed with the solution of PH=5.0-7.0, contain 10ug by every 2ml and calculate, make 1000 injection, detect with HPLC, after content is qualified, fill, sterilization meets medical sanitary standard or standard for animals, can use, be called for short: saxitoxin salt A.
Example 2, get N-STX, content (85-98%) 1mg is with oxalic acid 150 μ g, be mixed with the solution of PH=5.0-7.0, contain 10ug by every 2ml and calculate, make 1000 injection, detect with PLC, after content is qualified, fill, sterilization meets medical sanitary standard or standard for animals, can use, be called for short: N-STX B.
Example 3, get POP, content (85-95%) 1mg is with malic acid l50 μ g, be mixed with the solution of PH=5.0-7.0, contain 10ug by every 2ml and calculate, make 1000 injection, detect with PLC, after content is qualified, fill, sterilization meets medical sanitary standard or standard for animals, can use, be called for short: POP C.
Five, detect Fugu ocellatus toxin and saxitoxin instrument and reagent
1, instrument and reagent
1.1, Agilent type HPLC instrument, band UV detects and chromatographic work station Agela C
8Post or C
18Post, centrifuge, ultrasonic wave concussion extractor.
1.2, reagent: heptane base sodium sulfonate, phosphate buffer, HCN mobile phase, 0.01mM heptane base sodium sulfonate (PH=5.0 phosphoric acid)+1%HCN solution detects wavelength, UV-198nm; Flow velocity, 1.0ml/min; Sensitivity, 0.05ng/ml.
2, standard curve and concentration limit
Accurately weighed Fugu ocellatus toxin and saxitoxin thereof are an amount of, add the mobile phase dissolving and are diluted to the solution that contains Fugu ocellatus toxin 0.3,1.56,3.125,6.25,12.5,25,50 and 100 μ g/ml, shake up.Get respectively mentioned solution 20 μ l injection liquid chromatographies, triplicate is averaged, and the results are shown in Table 1.
Table 1 HPLC method is measured Determination of Tetrodotoxin and absworption peak area
Make linear regression with concentration and peak area, its linear equation is Y=42.012X+32.303, R
2=0.9997, X is concentration, and Y is peak area, shows Fugu ocellatus toxin in 0.3 ~ 100 μ g/ml concentration range, and concentration and its peak area are good linear relationship (Fig. 1).
Under experiment condition of the present invention, minimal detectable concentration is 0.07ng/ml.
3, the accuracy of method
The application of sample recovery test: precision takes by weighing hole tetrodotoxin and saxitoxin, joins the sample for high, medium and low three concentration, presses the HPLC content assaying method and measures, and according to standard curve determination content, calculate recovery rate the results are shown in Table 2.The result shows, the grand mean response rate of method is that 99.98%, SD is that the accuracy of 0.011, HPLC method is fine.
The application of sample recovery test: precision takes by weighing Fugu ocellatus toxin and saxitoxin, joins the sample for high, medium and low three concentration, presses the HPLC content assaying method and measures, and according to standard curve determination content, calculate recovery rate the results are shown in Table 2.The result shows, the grand mean response rate of method is that 99.98%, SD is that the accuracy of 0.011, HPLC method is fine.
?[0216]
4, the precision of method
The accurate Fugu ocellatus toxin solution of preparation 62 μ g/ml by the method continuous sample introduction of setting under the assay item 6 times, press standard curve calculating content, the results are shown in Table 3.
The Precision test result of table 3 method
The result shows that the precision of HPLC method assay is better.
Six, detection of antibiotics instrument and reagent
1, method one:
A, Waters-515 type HPLC instrument, band Uv and Electrochemical Detection and chromatographic work station, C
8Post or C
18Post, centrifuge, ultrasonic wave concussion extractor.
B, reagent: methanol (chromatographically pure), cyclohexane extraction, pyridine, ethanol, sodium hydroxide solution (0.55mol/l), hydrochloric acid solution (0.05mol/l). phosphoric acid and buffer thereof, acetic acid and buffer thereof.Agents useful for same is analytical pure, and institute's water meets GB.
C, (1) analytical column, ZORBAX C-18250nm * 250cm; Mobile phase, methanol, water (65: 35) detects wavelength, UV-220-263nm; Flow velocity, 0.65ml/min; Sensitivity, 0.01ng/ml.(2) analytical column, C-8 150nm * 2nm; Mobile phase, phosphate buffer (65: 35) detects wavelength, UV-220-283nm; Flow velocity, 0.5ml/min; Sensitivity, 0.01ng/ml.
D, standard curve and concentration limit
Take by weighing ciprofloxacin (quinolone antibiotic) 10mg in the 100ml measuring bottle, with the 0.1mol/l dissolving with hydrochloric acid and be settled to scale, shake up, be stock solution.Get in stock solution 1.0ml to the 100ml measuring bottle, use the hydrochloric acid standardize solution, shake up, be working solution.From working solution, get 1.0ml, 2.0ml, 4.0ml, 6.0ml, 8.0ml, 10.0ml in the 10ml measuring bottle, be diluted to scale with hydrochloric acid, shake up, concentration is respectively 0.1 μ g/ml, 0.3 μ g/ml, 0.5 μ g/ml, 0.8 μ g/ml, 1.0 μ g/ml, 1.2 μ g/ml, 1.5 μ g/ml
2.0 μ g/ml, sample introduction 20 μ l measure corresponding peak area respectively.Make linear regression with concentration and peak area, its linear equation is Y=4484531X+0.005579, R
2=0.9995, X is concentration, and Y is peak area, shows ciprofloxacin in 0.1 ~ 2.0 μ g/ml concentration range, and concentration and its peak area are good linear relationship.Under this paper experiment condition, minimal detectable concentration is 0.01ng/ml.
Table 4 HPLC method is measured ciprofloxacin content and absworption peak area
The accuracy of E, method
Application of sample recovery test: adopt standard addition method.Get and do not detect the blood sample that contains ciprofloxacin, detect again after quantitatively adding ciprofloxacin, with detected value divided by actual interpolation value, calculate recovery rate.Concrete operations are as follows: get negative blood sample 0.20g, and accurately weighed, put in the 100ml measuring bottle, accurately add a certain amount of reference substance working solution, mixing adds the about 70ml of hydrochloric acid solution, and soaked overnight is put 20min on the ultrasound wave shaker, be settled to scale with hydrochloric acid solution, shake up, leave standstill.Get the centrifugal 10min of supernatant (4000r/min), accurately draw supernatant 10.0ml, put separatory funnel, drip the sodium hydroxide solution alkalization, jolting 5min uses the cyclohexane secondary, and each 20ml merges the normal hexane layer, is settled to 50ml.Therefrom draw 5.0ml, put water bath method, accurately adding methanol is an amount of in residue, ciprofloxacin is fully dissolved, and make its concentration be about 0.2 μ g/ml～0.8 μ g/ml, through 0.45 μ filtering with microporous membrane, injects high-pressure liquid phase chromatograph measuring.Recording the response rate is 97.1%～98.8%, and the result is referring to table 5.
The table 5 sample average response rate and precision ± SD (n=5)
The precision of F, method
Get respectively matched group and do not inject each 2.0g of blood of the antibiotic complete lattice dog such as ciprofloxacin and rat, accurately weighed, put in the 100ml measuring bottle, add hydrochloric acid solution 70ml soaked overnight, below by the operation of response rate project approach, each is measured 5 times.Measurement result is that not inject the antibiotic blood such as ciprofloxacin entirely negative, has injected the antibiotic blood measuring average result 3.63ug/kg such as ciprofloxacin.CV is 1.8%.
Seven, screening antibiotic kind
1, kind: (1) ciprofloxacin, standard substance, labelled amount (98.5%) medicine inspecting institute buys.(2) tobramycin, standard substance, labelled amount (98.6%) medicine inspecting institute buys.(3) doxycycline, standard substance, labelled amount (95.2%) medicine inspecting institute buys.(4) acetylspiramycin, standard substance, labelled amount (98.5%) medicine inspecting institute buys.(5) rifampicin, standard substance, labelled amount (98.5%) medicine inspecting institute buys.(6) econazole, standard substance, labelled amount (98.5%) medicine inspecting institute buys.(7) amycin, standard substance, labelled amount (98.5%) medicine inspecting institute buys.(8) aciclovir, standard substance, labelled amount (97.5%) medicine inspecting institute buys.(9) enoxacin, standard substance, labelled amount (98.5%) medicine inspecting institute buys, (10) pyrazinamide, standard substance, labelled amount (98.5%) medicine inspecting institute buys.
2, experimental result:
Give respectively Canis familiaris L. and rat intramuscular injection or intravenous injection with Canis familiaris L. and the rat of antibiotic raising after 5 days such as injection ciprofloxacins with Fugu ocellatus toxin A, B, a, e, g saxitoxin A, N-stx-A, POP-A, animal injection TTX consumption is 0.1ug/Kg, then Canis familiaris L. and rat blood were got in 8 hours in the interval, surveyed the antibiotic content such as its ciprofloxacin.And compare with not injecting the antibiotic Canis familiaris L.s such as ciprofloxacin and rat blood.The results are shown in Table 6
Table 6 uses TTX-A, B, a, e, g and STX-A, N-stx-A, the average consumption 0.1ug/kg of POP-A detection limit ppm P＞0.01
[0244]?
Continued 6
[0247]?
2, method two, detection of antibiotics instrument and reagent
A, Waters-515 type HPLC instrument, band Uv and Electrochemical Detection and chromatographic work station, C
8Post or C
18Post, centrifuge, ultrasonic wave concussion extractor.
B, reagent: methanol (chromatographically pure), thiacyclohexane, pyridine, ethanol, sodium hydroxide solution (0.55mol/l), hydrochloric acid solution (0.05mol/l). phosphoric acid and buffer thereof, acetic acid and buffer thereof.Agents useful for same is analytical pure, and institute's water meets GB.
C, (1) analytical column, ZORBAX C-18 0.45um * 150nmX250cm; Mobile phase, methanol, water (65: 35) detects wavelength, UV-210-350nm; Flow velocity, 1.0ml/min; Sensitivity, 0.01ng/ml.
(2) analytical column, Agel C-8 0.45um * 150nm * 250cm; Mobile phase, phosphate buffer (65: 35) detects wavelength, UV-210-420nm; Flow velocity, 1.0ml/min; Sensitivity, 0.01ng/ml.
D, standard curve and concentration limit
Take by weighing the antibiotic reference substance 10mg such as penicillin in the 100ml measuring bottle, with the 0.1mol/l dissolving with hydrochloric acid and be settled to scale, shake up, be the reference substance stock solution.Get in reference substance stock solution 1.0ml to the 100ml measuring bottle, use the hydrochloric acid standardize solution, shake up, be the reference substance working solution.From working solution, get 1.0ml, 2.0ml, 4.0ml, 6.0ml, 8.0ml, 10.0ml in the 10ml measuring bottle, be diluted to scale with hydrochloric acid, shake up, concentration is respectively 0.1 μ g/ml, 0.2 μ g/ml, 0.4 μ g/ml, 0.6 μ g/ml, 0.8 μ g/ml, 1.0 μ g/ml, and sample introduction 20 μ l measure corresponding peak area respectively.When penicillin concn during at 0.1 μ g/ml～1.0 μ g/ml scope, concentration is good with corresponding peak area linear relationship, and regression equation is Y=4484531X+0.005579, and correlation coefficient is 0.9995.Under this paper experiment condition, minimal detectable concentration is 0.05 μ g/ml.
E, recovery test
Adopt standard addition method.Get and do not detect the blood sample that contains penicillin, detect again after quantitatively adding penicillin, with detected value divided by actual interpolation value, calculate recovery rate.Concrete operations are as follows: get negative blood sample 0.20g, and accurately weighed, put in the 100ml measuring bottle, accurately add a certain amount of reference substance working solution, mixing adds the about 70ml of hydrochloric acid solution, and soaked overnight is put 20min on the ultrasound wave shaker, be settled to scale with hydrochloric acid solution, shake up, leave standstill.Get the centrifugal 10min of supernatant (4000r/min), accurately draw supernatant 10.0ml, put separatory funnel, drip the sodium hydroxide solution alkalization, jolting 5min uses the cyclohexane secondary, and each 20ml merges the normal hexane layer, is settled to 50ml.Therefrom draw 5.0ml, put water bath method, accurately adding methanol is an amount of in residue, penicillin is fully dissolved, and make its concentration be about 0.2 μ g/ml～0.8 μ g/ml, through 0.45 μ filtering with microporous membrane, injects high-pressure liquid phase chromatograph measuring.Recording the response rate is 89.5%～96.1%, and the result is referring to table 7.
Table 7 determination of recovery rates result (n=5)
Get respectively matched group and do not inject each 2.0g of blood of the antibiotic beasle dog such as penicillin and rat, accurately weighed, put in the 100ml measuring bottle, add hydrochloric acid solution 70ml soaked overnight, below by the operation of response rate project approach, each is measured 5 times.Measurement result is that not inject the antibiotic blood such as penicillin entirely negative, has injected the antibiotic blood measuring average result 3.63ug/kg such as penicillin.CV is 4.6%.More than the proof experimental apparatus is reliable.
Eight, the antibiotic kind of Na-ion channel blocker antagonism
1, kind: (1) penicillin V, standard substance, labelled amount (95.5%) medicine inspecting institute buys.(2) tobramycin, standard substance, labelled amount (98.6%)
Medicine inspecting institute buys.(3) doxycycline, standard substance, labelled amount (94.2%) medicine inspecting institute buys.(4) acetylspiramycin, standard substance, labelled amount (98.5%) medicine inspecting institute buys.(5) rifampicin, standard substance, labelled amount (91.5%) medicine inspecting institute buys.(6) econazole, standard substance, labelled amount (91.5%) medicine inspecting institute buys.(7) amycin, standard substance, labelled amount (91.5%) medicine inspecting institute buys.(8) aciclovir, standard substance, labelled amount (91.5%) medicine inspecting institute buys.(9) enoxacin, standard substance, labelled amount (91.5%) medicine inspecting institute buys.(10) pyrazinamide, standard substance, labelled amount (91.5%) medicine inspecting institute buys.
2, experimental result:
Give respectively Canis familiaris L. and rat intramuscular injection or intravenous injection with Canis familiaris L. and the rat of the antibiotic such as penicillin raising after 5 days with Fugu ocellatus toxin TTX-A, saxitoxin STX-A, average T TX consumption 0.05ug/Kg, then Canis familiaris L. and rat blood were got in 8 hours in the interval, surveyed the antibiotic content such as its penicillin.And compare with not injecting the antibiotic Canis familiaris L.s such as penicillin and rat blood.The results are shown in Table 8
Table 8 uses the average consumption 0.05ug/kg of TTX-A, STX-A detection limit ppm P＞0.01
Nine, the pathogenic bacterial drug resistance detects
1, Acinetobacter bauamnnii drug susceptibility test.Adopt the KB disk diffusion method.Operating result judges that reading is in strict accordance with 2004 editions criterions of U.S. clinical experiment standardization committee (NCCLS).
A, instrument, VITEK-32 full automatic microorganism analyser.
B, susceptibility paper are available from Beijing Tiantan Bio-pharmaceuticals technology development co..
C, Grain-negative identification plate (GNI+) identify strain.
D, control strain are available from Ministry of Public Health visiting center.Result of study sees Table 9
Table 9,656 strain Acinetobacter bauamnniis are to clinical common antibiotics resistant rate with the resistant rate after using TTX, STX
[0275]?
2, the drug susceptibility test of enterobacter cloacae.Adopt the KB disk diffusion method.Operating result judges that reading is in strict accordance with 2004 editions criterions of U.S. clinical experiment standardization committee (NCCLS).
A, Antibiotic discs: ampicillin (AM), piperacillin (PIP), ceftazidime (CAZ), cefotaxime (CTX), ceftriaxone (CRO), cefepime (FEP), ciprofloxacin (CIP), levofloxacin (LEV), amikacin (AK), safe energy (IMP), aztreonam (ATM), Obramycin (TB), bactrim (SXT) are purchased Beijing microorganism reagent company limited.
B, M
+The H culture medium is purchased from Beijing microorganism company limited.
C, contrast strain, escherichia coli ATCC25923, Pseudomonas aeruginosa ATCC2783, staphylococcus aureus ATCC259233 is available from the Clinical Laboratory center.
D, Drug Resistance Detection: (1), super broad ectrum antibiotic EsBLs detect, and bacterial clump is diluted to the bacterium liquid of 0.5mm Maxwell turbidity, evenly are coated with the end in M
-On the H flat board, stick in the antibiotic susceptibility paper such as ceftazidime, hatch 24hr (37C), if antibiotic average antibacterial ring≤2-27mm can be judged as the generation of EsBLs enzyme.(2), the detection of AMPC enzyme: bacterial clump is become 0.5mm Maxwell turbidity with normal saline dilution, evenly is applied on the M-H flat board, paste 1 various antibiotic drug sensitive test paper such as cefoxitin, when inhibition zone diameter is≤8-21mm, both suspicious for producing the Ampc enzyme.Experimental result sees Table 10,
Table 10, common antibiotics are to 225 Enterobacter cloacae resistant rate with the resistant rate after using TTX, STX
[0283]?
3, the drug resistance of Klebsiella Pneumoniae (KPN) detected.Operating result judges that reading is according to 2004 editions criterions of U.S. clinical experiment standardization committee (NCCLS).
A, susceptibility test methods.
Adopt VitekGPS-101 susceptibility card (French Biomerieux SA product).Carry out data statistics analyse with the Vitek statistical software.Resistant rate to 351 strain KPN and AEEF antibacterial sees Table 11.
The KPN specimen of table 11 separate sources is to the resistant rate of common antibiotics and the resistant rate behind use TTX, the STX
[0289]?
4, Bulbus Allii Cepae Burkholder drug resistance being detected. operating result judges that reading is according to 2004 editions criterions of U.S. clinical experiment standardization committee (NCCLS).
A, susceptibility test methods.Susceptibility paper is Britain Oxoid company, data analysis WHONET-5 software.Drug resistance testing result to common antibiotics sees Table 12.
Table 12, Burkholderia cepacia is to the resistant rate of common antibiotics and TTX
[0294]?
5, the drug resistance of helicobacter pylori detected.Detect with the Etst method.
A, strains separation grind biological tissue with dismembyator, drip 0.5ml and pass on liquid, be inoculated in respectively 8% Colombia (Britain OXOID) blood agar plate and add SR147E, 37C, humidity 90%, cultivated 3-5 days, and chose translucent petite and identify.
B, drug sensitive test, get 72hr tradition culture HP product in BH1 meat soup (bio-Merieux outside the France) pipe, the allotment bacterial concentration is to 1.0Mc, get 100 μ l bacterium liquid in diameter 90mm with sample injector, on the blood agar plate of thickness 4+0.5mm, with Glass rod coating evenly, place 10min and be placed with at agar surface with Etest strip (Sweden AB BIODISK), read the MIC value in the point of interface of the antibacterial ring of ellipse and strip.The results are shown in Table 13.
Table 13, the resistant rate of helicobacter pylori, antibiotic and TTX
6, enterococcus faecalis (AREF) drug resistance is detected, operating result judges that reading is according to 2004 editions criterions of U.S. clinical experiment standardization committee (NCCLS).
A, susceptibility test methods.
Adopt VitekGPS-101 susceptibility card (French Biomerieux SA product).Carry out data statistics analyse with the Vitek statistical software.Resistant rate to 351 strain KPN and AEEF antibacterial sees Table 14.
Table 14 enterococcus faecalis (AREF), TTX are to antibiotic resistant rate
[0305]?
7, the research of methicillin-resistant staphylococcus aureus (MRSA)
Methicillin staphylococcus aureus (MRSA) drug resistance is detected, and operating result judges that reading is according to 2004 editions criterions of U.S. clinical experiment standardization committee (NCCLS).
A, susceptibility test methods.
Adopt VitekGPS-101 susceptibility card (French Biomerieux SA product).Carry out data statistics analyse with the Vitek statistical software.Resistant rate to 851 strains (MRSA) antibacterial sees Table 14.
Table 15 methicillin staphylococcus aureus (MRSA) and TTX are to antibiotic resistant rate
8, share the research that improves titer of antibodies with antibiotic
A, select the antibiotic kind: ampicillin, ciprofloxacin, aztreonam, Zinacef.
B, select strain: methicillin staphylococcus aureus, enterococcus faecalis (AREF), Pseudomonas aeruginosa ATCC2783, escherichia coli ATCC25923, staphylococcus aureus ATCC259233.Available from the Clinical Laboratory center.
C, sterilization rate detect: with the bacterium liquid that Bacteria planting number calculates, evenly be coated with the end in M
-On the H flat board, compare group, will add in the antibiotic medicine of Fugu ocellatus toxin and saxitoxin (1mg/ml), hatch 24hr (37C), calculate antibiotic average bacteriostasis rate (strain number), with not adding TTX and the STX sample compares group, experimental result sees Table 15
The bacteriostasis rate that table 15 antibiotic and TTX, STX share
Continued 15
[0320]?
Above experimental result confirms, Na-ion channel blocker of the present invention is prepared into medicine or health product, can improve significantly antibiotic drug effect and treatment Antibiotic resistance problem.
Brief Description Of Drawings: Fig. 1 is the linear relationship of Fugu ocellatus toxin detectable concentration and content.
List of references
[1]Christian?Raetz?at，Journal?of?Biological?Chemistry(9-17-2001)
[2 Chen Hong ice etc., practical medical technologies magazine the 20th phase of October in 2006,3583-3584
[3] Li Wenbo etc., international laboratory medicine magazine the 10th phase of October in 2006,943-945
[4]Anderson?DM，White?AW，Baden?DG.Factors?significant?to?marine?dinoflagellate?culture.KellerMD，GuillardRRL，Toxic?Dinoflagellates[M].New?York，Elsevier，1985.Il3-Il6
[5]Andrew?Hinman?and?J?Du?Bois，J，AM.CHEM.SOC.2003，125，11510-11511
[6]Bates?HA，Raport?H.A?chemical?assay?for?satitoxin，theparalytic?shellfish?poison?FoodChem，1975，23(2)：237-239.
[7] Song jj, Miao QW.Toxicology ofMarine Organism (marine biotoxins) [M] .Beijing:BeijingScience[5] ﹠amp; TechnologyPress, 1996.
Claims (3)
1. have general formula (I), (II), (III), (IV), (V) and sodium ion channel antagonist compound (VI) in the purposes of the medicine of preparation reduction antibiotic resistance purposes,
(I) under the solid state
Wherein, R
1=R
2=R
4=R
5=OH R
3=CH
2OH; (Fugu ocellatus toxin)
R
1＝R
3＝R
4＝R
5＝OH，R
2＝CH
2OH；
(m) under the liquid condition
Wherein: R
1=R
2=R
4=R
5=OH, R
3=CH
2OH; (Fugu ocellatus toxin lactone)
R
1＝R
3＝R
4＝R
5＝OH，R
2＝CH
2OH；
(IV)
Wherein: R1=R2=R4=R5=OH, R3=CH2OH; (4-shows Fugu ocellatus toxin)
R1＝R3＝R4＝R5＝OH，R2＝CH2OH：
(V)
Wherein,
R1=H, R2=R4=R5=OH, R3=CH2OH; (deoxidation Fugu ocellatus toxin)
R1＝H，R3＝R4＝R5＝OH，R2＝CH2OH；
(VI)
Wherein: in the formula: R1=R2=R4=R5=OH, R3=C12OH, R=H; Tetrodonic acid
R1＝R3＝R4＝R5＝OH，R2＝CH2OH，R＝H；
(II)
In the formula: R1=R 2=R 3=R 4=H saxitoxin (STX).
2. purposes according to claim 1, it is characterized in that: described antibiotic is selected from penicillins, cephalosporins, aminoglycosides, Tetracyclines, chloromycetin, Macrolide or lincomycin class.
3. purposes according to claim 1 is characterized in that: said pharmaceutical dosage form is that injection, oral formulations, skin stick agent, supp anal, spray or oil formulation.
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