CN100493513C - Application of 4-de-dimethyltetracycline derivative - Google Patents
Application of 4-de-dimethyltetracycline derivative Download PDFInfo
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- CN100493513C CN100493513C CNB031269508A CN03126950A CN100493513C CN 100493513 C CN100493513 C CN 100493513C CN B031269508 A CNB031269508 A CN B031269508A CN 03126950 A CN03126950 A CN 03126950A CN 100493513 C CN100493513 C CN 100493513C
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Abstract
The invention refers to the application of 4-deminocycline ramification to the preparation of drugs of anti-SARS, antivirus, anti-leptospira, anti-mycobacterium, etc; a medicinal combination for curing SARS contains effective amount of 4-deminocycline ramification and medicinal carrier; the invention has the application advantage of 4-deminocycline ramification able to prevent and cure the infection caused by virus ( SARS coronary virus), leptospira and mycobacterium (including mycoplasma and chlamydia).
Description
Technical field
The present invention relates to the application that a kind of 4-removes the dimethylamino tetracycline derivant.
Background technology
Tetracycline (Tetracyclines) is found to be the broad-spectrum bacteriostatic, and (i.e. growth to Gram-positive and negative bacteria all has inhibitory action, but can not killing bacteria), be the antimicrobial drug that is produced by antibacterial Streptomyces aureofaciens, main antibacterial action is synthetic by suppressing protein of bacteria.Its bacteriostasis mechanism is: the tetracycline molecule enters the small subunit (being the 30S subunit) that is attached to bacterial ribosome in the antibacterial, identification and pairing between the codon of the anticodon of aminoacyl-tRNA and mRNA have directly been influenced, thereby stop protein synthesis in the antibacterial, cause the antibacterial breeding that stops growing.Under the intravital immune system effect of people, dormant antibacterial can be eliminated by leukocyte, thereby reaches recovery from illness.Tetracycline parent nucleus (Fourth Ring structure) has very strong fat-soluble, is that such medicine enters bacterial cell and be attached in the bacterial cell target structure (targeted components) institute necessary.Each group on the tetracycline parent nucleus has different effects to antibiotic, wherein with the 4-dimethylamino (the 4th-N (CH
3)
2Having the greatest impact group).Studies have shown that of past, the tetracycline molecule (that is: 4-removes the dimethylamino tetracycline) of removing the 4-dimethylamino loses the antibacterium ability more than 90%.
Virus is the protoplasm granule of a class no cell structure, only is made up of hereditary material (nucleic acid) and protein.Virus is carried out self-replication by after entering human body cell by intracellular biosynthesis system (as the synthesis system of protein and nucleic acid), the normal function of influence simultaneously or destruction cell, even kill host cell to reach diffusion and to cause pathological change.Disorganization that a lot of viral infection cause (as hepatitis etc.) or hypertrophy (as venereal wart condyloma acuminata etc.), mainly be because infected host cell expression some virus antigens, cause partial cell immune response (inflammatory reaction), histiocyte destruction, fibrosis and unusual hyperplasia.Over-drastic inflammatory reaction is the key factor that viral infection causes histoorgan forfeiture normal physiological function even patient's death.Because still not having specific antiviral drugs at present can enter duplicating of the interior prevention virus of cell and suppress its toxicity, so general Therapeutic Method is the too drastic immunoreation (as steroid hormone) of control, promote the cleaning (as interferon) of infected cell, and supporting treatment (as trophotherapy) etc.But the effect of these therapies is not ideal.
Spirillum is the very strong wire microorganism of activeness, can be hosted by in tissue, blood, the juice.Spirillum usually causes digestive tract, urinary system, reproductive tract, and the acute and chronic infection of respiratory tract and general, wherein the chronic gastritis that is caused by spirillum is a kind of very common chronic gastropathy, course of disease decades-long.Spirillum also can be invaded cell, destroys the function of cell even kills the boarding cell.One of morbific mechanism of spirillum is the inflammatory reaction that the interaction between host and pathogen causes, and comprises the activation of immunocyte and the release of inflammatory factor (as TNF-α and IL-1 β etc.), and leukocytic rapid collection and disorganization.Antibiotics (as penicillin treatment syphilis) is mainly used in spirochetotic treatment.But some spirochetosis is very obstinate, and for example chronic gastritis that is caused by spirillum, chronic cervicitis etc. may be because these spirillums have produced drug resistance, and perhaps these pathogen have entered host cell and escaped due to the attack of medicine.
Mycobacteria (comprise mycoplasma and according to substance) is the pathogenic microorganism between virus and antibacterial.Because this type of cause of disease physical ability enters human body cell, and is easy to generate drug resistance to general antibiotics, that its disease that causes is difficult to effect a radical cure often is chronic, repeated relapsing inflammation and disorganization.Because this class pathogen enters the change that causes cell surface antigen behind the host cell, the interaction of infected cells and immunocyte causes immunoreation, cause the rapid collection (mainly being leukocytic infiltration) of local organization inflammatory cell, even formation tuberosity, general medicine is difficult to enter tuberosity tissue effectively or to enter infected host cell and kill this class pathogen, is to cause the chronic one of the main reasons with repeated relapsing of this type of disease.To mycoplasma with use antibiotics (as acetylspiramycin etc.) usually according to the treatment of substance disease.Yet, produce chemical sproof tuberculosis for some and must use the very big two wires medicine of toxicity (as rifampicin etc.).Therefore, need multiple medicine to be used alternatingly to such treatment of diseases to reduce its chemical sproof generation.
In sum, virus, spirillum and mycobacteria (comprise mycoplasma with according to substance) etc. directly activate host's immune system and cause the inflammatory reaction except being present in the extracellular, can also invade host cell and influence the metabolism and the function of cell, and cause inflammatory reaction indirectly by the surface antigen that changes infected cell.In inflammatory reaction and disorganization process that these pathogen cause, inflammatory factor (as TNF-α and IL-1 β etc.) and matrix metalloproteinase (Matrix Metalloproteinase that the host cell that is activated (being inflammatory cell) discharges, MMP is as collagenase) play critical effect.Ideal medicine except toxicity little and can reduce inflammation the reaction, can also suppress or pathogen kill, particularly can enter the host cell eliminating pathogen.
Summary of the invention
Purpose of the present invention just provides the application that 4-that a kind of infection that virus (comprising the coronavirus that causes SARS), spirillum and mycobacteria (comprise mycoplasma with according to substance) are caused has preventive and therapeutic effect removes the dimethylamino tetracycline derivant.
The object of the present invention is achieved like this: 4-goes the dimethylamino tetracycline derivant to prepare application in the medicine of anti-SARS virus.
Purpose of the present invention can realize like this: 4-goes the dimethylamino tetracycline derivant to prepare application in the antiviral drug.
Purpose of the present invention can also realize like this: 4-goes the dimethylamino tetracycline derivant to prepare application in the antispirochetic medicine.
Purpose of the present invention also can also realize like this: 4-goes the dimethylamino tetracycline derivant to prepare application in the medicine of anti-mycobacteria.
Purpose of the present invention can realize again like this: 4-goes the dimethylamino tetracycline derivant to prepare application in the medicine of antitoxin mass formed by blood stasis.
Purpose of the present invention also can realize like this: 4-goes the dimethylamino tetracycline derivant to prepare application in the medicine of anti-skin pruritus.
Purpose of the present invention can also realize like this: a kind of Pharmaceutical composition that is used for the treatment of SARS, the described 4-of claim 1～6 that it contains effective dose removes dimethylamino tetracycline derivant and pharmaceutical carrier.
4-of the present invention goes the dimethylamino tetracycline derivant to have the molecular structure shown in Fig. 1 and the table 2.
Since the hydrophilic effect that the 4-dimethylamino has, thus make 4-go dimethylamino tetracycline derivant fat-soluble (or vegetables aqueous) to compare remarkable increase with tetracycline, also increased their ability that enters cell (Fig. 2, table 1) simultaneously.4-goes dimethylamino fairy ring element (4-dedimethylamino sancycline) to lose dimethylamino (hydrophilic group) and the 6th the 4th of parent nucleus and loses hydroxyl (hydrophilic group) and methyl, all increases (table 2, table 1) greatly of ability that it is fat-soluble and enter cell, this is that this medicine enters the important feature that cell plays a role.4-goes the antifungic action of dimethylamino tetracycline derivant relevant with their fat-solubility, because the cell membrane of the antibacterial that fungal cell's wall construction is more general (or folder film) structure is more complicated, chitin (Chitin) as fungus has important effect in the fungal cell wall function, the influence that medicine is entered the fungal cell is very big.And 4-goes the dimethylamino tetracycline derivant can enter the fungal cell in a large number, its antifungic action be likely by in conjunction with and suppress intracellular organelle (as mitochondrion etc.) and the function of some enzyme is achieved.
4-goes the dimethylamino tetracycline derivant to also have an important biological action, promptly to metalloproteases (Metalloproteinase, inhibitory action MP).This analog derivative is extensively thought to have antiinflammatory action to the inhibition of MP, and (as Collagenase etc.) is the key factor that causes disorganization and pathogen diffusion to the Degradation of inflammation histone because the metalloproteases that host cell and pathogen (as antibacterial) discharge in inflammation.Simultaneously, some metalloproteases also is the key factor that some interleukins (as tumor necrosis factor TNF-alpha) generate and discharge.
4-goes the foundation of dimethylamino tetracycline derivant as antiviral, anti-spirillum and anti-mycobacteria (comprise mycoplasma and according to substance) medicine, mainly comprise two aspects: (a) antiinflammatory action of this analog derivative and suppress metalloproteases to the Degradation of tissue protein (Fig. 3, Fig. 4); (b) ability (table 1, Fig. 2) of the fat-soluble and penetrate tissue cell membrane of the height that has of this analog derivative may directly enter infected cell and suppress even pathogen kill, acts on thereby reach treatment (or radical cure).
Some 4-goes person monocytic cell (Monocyte) that the dimethylamino tetracycline derivant can effectively suppress to cultivate at lipopolysaccharide (Lipopolysaccharide, LPS) stimulate generation TNF-α down, inflammatory factors (Fig. 4) such as interleukin I L-1 β, these effects can both reduce the too drastic inflammatory reaction of human body to pathogen and toxin (as LPS) thereof effectively, thereby reduce inflammation the disorganization degree, help the recovery of inflammation tissue.
Because 4-goes the dimethylamino tetracycline derivant can enter cell (Fig. 2) effectively and suppresses wherein some organelles and the function of some enzyme, this just helps this medicine inhibition virus replication or scavenger cell inner virus, thereby reaches antivirus action.
4-removes the dimethylamino tetracycline derivant and discharges inflammatory factor (as TNF-α and IL-1 β etc.) and matrix metalloproteinase (MMP) activity owing to can suppress host cell, thereby alleviates inflammatory reaction and the disorganization that spirillum causes greatly.In addition, 4-goes the dimethylamino tetracycline derivant to have fat-solubility and penetrates into the characteristics of cell easily, also may have to suppress the spirillum growth even kill this action of microorganisms, thereby have the medical value of the disease that treatment causes by spirillum.Experiment shows, goes the plain insulation of dimethylamino fairy ring (37C) after 12 hours with 4-, and 100% spirillum (Spirocheteborreba kurgdorferi) is eliminated, and this explanation tetracycline derivant may have this spirochetal effect (Fig. 5) of killing.
Such tetracycline derivant is by the inflammation-inhibiting factor (TNF-α, interleukin I L-1 β etc.) generation and alleviate overactive immune response (acute stage) and the chronic inflammatory reaction that mycobacteria is caused effectively simultaneously also may be by infiltrating tuberosity tissue or entering the growth and breeding of inhibition pathogen in the cell of infection.
Such tetracycline derivant is except the inflammation-inhibiting factor discharges effectively, and it suppresses the Degradation of metalloproteases (as MMP) to histone effectively, is one of mechanism that alleviates or extinguish the skin pruritus that is caused by inflammation.
Find that in China also popular severe acute respiratory syndrome is the acute respiratory syndrome (SARS) that is caused by coronavirus at present.This sick seriousness is the caused over-drastic acute inflammatory reaction of virus (causing that as toxemia a large amount of inflammatory factors discharge in the body, particularly TNF-α and IL-1 β etc.), causes the lung tissue heavy damage, causes patient respiratory difficulty even dead.Steroid hormone has positive effect for alleviating the destructiveness and the reduction mortality rate of this disease to pulmonary, utilizes the antiinflammatory action of steroid hormone exactly.But because steroid hormone suppresses patient's immune system simultaneously, its side effect is self-evident.Different with steroid hormone, it is not by suppressing immune system that 4-removes the antiinflammatory action of dimethylamino tetracycline derivant, but the directly release of the inflammation-inhibiting factor, thereby reduce the chemical chemotaxis (promptly shifting to inflammation part) of inflammatory cell (mainly being the leukocyte that is activated) and the infiltration of inflammatory cell by inflammatory factor guiding leukocyte.In addition, 4-goes the dimethylamino tetracycline derivant can suppress the MMP activities (MMP of periplast very effectively, leukocyte can discharge the degraded that this fermentoid causes tissue protein after destroying in a large number), directly reduce the inflammation disorganization, must have therapeutical effect to SARS.Simultaneously, such medicine also may enter by the host cell of viral infection, and that suppresses virus duplicates even kill virus, has huge application potential for reducing this sick infectiousness.
Tetracycline derivant be with the tetracycline parent nucleus serve as the basis through chemical improvement and deutero-a series of chemical compound, in respect of several thousand kinds, wherein have and utilize the only a few that is worth.The present invention is based on the following fact: 4-and goes the dimethylamino tetracycline derivant to lose all or part of antibacterium function, and fat-soluble increase of its molecule (increase of permeates cell membranes function) and antifungal, anti-metalloproteases function also significantly increase.Use 4-to remove dimethylamino Tetracyclines medicine, can prevent that on the one hand the Drug resistance that the antibacterium medicine causes usually from occurring and causing bounce-back property bacterial infection (because of antibacterial other microorganism is had inhibitory action or/and the unbalance sexuality of other microorganisms (as fungus) is dyed, other pathogen loses restriction and breeds in a large number and cause a disease after normal bacteria is by severe inhibition), can utilize the antiinflammatory and the anti-metalloproteases effect of these derivants to alleviate virus on the other hand, inflammatory reaction and disorganization that spirillum and mycobacteria cause, and utilize its fat-solubility characteristics to enter cell, disturb or stop the breeding of above-mentioned pathogen or duplicate, to reach the purpose that may suppress or kill these pathogen (being included in the cell).So patent of the present invention is only limited to 4-and removes the dimethylamino tetracycline derivant, and the pharmaceutical carrier of forming by these derivants.Application (comprising the application that prevents and treats the aspect) for above-mentioned listed pathogenic microorganism, this class medicine has the therapeutical effect of working along both lines, and (that is: both can suppress pathogen breeds or duplicates, the inflammatory reaction that suppresses pathogen again and caused) and prevent the characteristics that the resistance bounce-back is infected.
Because above-mentioned listed pathogen has the ability of invasion cell, cause general medicine to be difficult to thoroughly treat this class disease, acuteness condyloma latum (viral infection) for example, some chronic gastritis (gastritis spirillum), and the severe acute respiratory syndrome that causes according to substance or mycoplasma etc., at present this class treatment of diseases be there is no specific medicament, and can be for the medicament categories for the treatment of use seldom.So the present invention for these diseases may provide one brand-new, means of prevention not only has huge business potential efficiently, and has far-reaching medical research meaning.
The present invention: 1, part and the systemic infection that virus is caused: (a) viral vegetation is [as verruca plana, acuteness condyloma latum (venereal wart condyloma acuminata), polyposis intestinalis etc.], (b) virus infected herpes is (as herpes zoster, oral cavity or dermal viral herpes etc.), (c) general viral infection (, comprising the deadly infectious disease SARS that finds in China at present, viral meningitis etc.) as viral pneumonia;
2, part and the systemic infection that spirillum is caused: local infection (as the spirochaete infection of respiratory tract, digestive tract, reproduction and urinary tract), systemic infection (as through the spirochaete infection of blood diffusion etc.);
3, part that mycobacteria is caused and systemic infection (as by mycoplasma or the skin that causes according to substance, respiratory tract, digestive tract, urinary system and reproductive tract infection, or general mycobacterial infections etc.);
4, to toxemia (toxemia that causes as antibacterial, viral infection, as finding in China at present deadly infectious disease SARS);
5, the skin pruritus that inflammation is caused (as nerve, infectivity, contact dermatitis etc.);
All has preventive and therapeutic effect, that is: the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete.
When being used as medicine for external use, its effective dose (percentage by weight) 0.01～5% of a., fat-soluble medium 95～99.99%; B. its effective dose (percentage by weight) 0.01～5%, emulsifying agent 0.0001～0.5%, water 94.5～99.99%.
When being used as oral medicine, its effective dose (percentage by weight) 90～99%, sugar-coat 1～10%.
When being used as injection, its effective dose (percentage by weight) 0.1～10% of a., sodium chloride 0.9～1%, water 89～99%; B. its effective dose (percentage by weight) 0.1～10%, glucose 5～10%, water 80～94.9%; C. its effective dose (percentage by weight) 0.1～10%, sodium chloride 0.9～1%, glucose 5～10%, water 79～94%.
Description of drawings
Fig. 1 is the structural representation of tetracycline derivant molecule of the present invention,
Fig. 2 goes the dimethylamino tetracycline derivant to enter in the person monocytic cell for 4-of the present invention,
Fig. 3 is a HPLC collection of illustrative plates of the present invention,
The repressed collection of illustrative plates of inflammatory factor that Fig. 4 causes at lipopolysaccharide (LPS) for the present invention,
The collection of illustrative plates that Fig. 5 is eliminated at spirillum for the present invention.
The specific embodiment
The present invention is described in further detail below in conjunction with drawings and Examples:
As shown in Figure 1, work as R
1R
2R
3R
4R
5R
6R
7When being different group, its tetracycline derivant is respectively listed as table 2.
As shown in Figure 2, the demonstration of laser electron-microscope scanning collection of illustrative plates, 4-go dimethylamino fairy ring element and the insulation of person monocytic cell's suspension after 2 hours, be found and enter cell interior (fluorescence in the cell is produced by this medicine) in a large number.
As shown in Figure 3, the HPLC collection of illustrative plates shows, A: the octapeptide (DNP-OP, similar human collagen peptide chain) that the metalloproteases that extracts from yeast can the hydrolysis synthetic, B: after adding 4-and removing dimethylamino fairy ring element, the hydrolysis of this enzyme is subjected to remarkable inhibition.
As shown in Figure 4, person monocytic cell's release tumor necrosis factor (TNF-α) and il-1 (IL-1 β) are subjected to 4-to go the inhibition of dimethylamino fairy ring element (C3) under lipopolysaccharide (LPS) stimulates.(A: work as C3=5, during 10 μ g/ml to the inhibition of TNF-α; B: work as C3=2.5, during 5.0 μ g/ml to the inhibition of IL-1 β; Dxy is plain for the ring of thinking much; Cx is the tetracycline derivant of unknown structure).
As shown in Figure 5, spirillum (Spirochete borreba kurgdorferi) and 4-go dimethylamino fairy ring element (C3) insulation (37 ℃) after 24 hours, and the spirillum quantity alive of examining under a microscope every visual field drops to 0 from 8, and its IC50 is less than 1 μ g/ml.Cx is the tetracycline derivant of unknown structure.
It contains effective dose 0.01% during medicine for external use, and fat-soluble medium vaseline 99.99%, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 5% during medicine for external use, and fat-soluble medium tristerin 95%, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 0.05% during medicine for external use, and fat-soluble medium sodium laurylsulfate 99.95%, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 1% during medicine for external use, and fat-soluble medium white vaseline 99%, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 2% during medicine for external use, and fat-soluble medium pyrene Oleum Sesami 98%, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 3% during medicine for external use, and the liquid paraffin wax 97% of fat-soluble medium, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 4% during medicine for external use, and fat-soluble medium lanoline 96%, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 2.5% during medicine for external use, and fat-soluble medium sodium laurylsulfate 97.5%, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 0.01% during medicine for external use, and emulsifying agent phosphatidase 10 .0001%, water 99.9899%, common process make external and reach antiviral, anti-spirillum, the effect of anti-mycobacteria.
It contains effective dose 5% during medicine for external use, and emulsifying agent sodium stearate 0.05%, water 94.95%, common process are made external and reached antiviral, anti-spirillum, the effect of anti-mycobacteria.
During oral medicine its to contain effective dose be 90%, sugar-coat 10%, common process is made, and takes and reaches the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete.
During oral medicine its to contain effective dose be 99%, sugar-coat 1%, common process is made, and takes and reaches the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete.
Embodiment 13
Injecting drug use contains effective dose 0.1%, sodium chloride 1%, and water 98.9%, common process is made, and reaches the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete after the injection.
Embodiment 14
Injecting drug use contains effective dose 10%, sodium chloride 0.9%, and water 89.1%, common process is made, and reaches the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete after the injection.
Injecting drug use contains effective dose 0.1%, glucose 10%, and water 89.9%, common process is made, and reaches the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete after the injection.
Embodiment 16
Injecting drug use contains effective dose 10%, glucose 5%, and water 85%, common process is made, and reaches the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete after the injection.
Embodiment 17
Injecting drug use contains effective dose 0.1%, sodium chloride 1%, and glucose 10%, water 88.9%, common process is made, and reaches the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete after the injection.
Embodiment 18
Injecting drug use contains effective dose 10%, sodium chloride 1%, and glucose 10%, water 79%, common process is made, and reaches the effect of antiviral, anti-SARS, anti-spirillum, anti-mycomycete after the injection.
In embodiment 1～18, the release of interleukin such as the factor such as TNF-α, IL-1 β and metalloproteases because viral infection can cause inflammation, cause inflammatory reaction and disorganization (as SARS), therefore, release and the MMP activities of TNF-α, IL-1 β when checking 4-goes the dimethylamino tetracycline derivant to suppress viral infection, promptly represent the pathological change when it can alleviate viral infection, that is: the clinical symptoms when alleviating viral infection; Add 4-and go the dimethylamino tetracycline derivant to cultivate, can verify 4-goes the dimethylamino tetracycline derivant whether to suppress the growth of this mycobacteria with mycobacteria; Add 4-and go the dimethylamino tetracycline derivant to cultivate with spirillum, the spirillum quantity that the reuse microscopic examination is lived reduces situation, can verify 4-goes the dimethylamino tetracycline derivant whether to suppress the growth of this pathogen.
Table 1:4-goes the fat-soluble of dimethylamino tetracycline derivant and enters person monocytic cell's situation.
Table 2:4-goes the important group of dimethylamino derivant to distribute.
Table 1,4-go the fat-soluble of dimethylamino tetracycline derivant and enter person monocytic cell's situation *
*Cx: unknown structure tetracycline derivant; C3:4-removes dimethylamino fairy ring element; C4:4-removes the dimethylamino duomycin.
Table 2, several 4-as to go the important group of dimethylamino tetracycline derivant distribute (Fig. 1 is seen in the position of R)
Claims (3)
1,4-goes the purposes of dimethylamino fairy ring element aspect preparing the medicine that suppresses to infect in the cell, infect in the described cell and cause by spirillum, infect in the described inhibition cell by suppressing spirillum in intracellular breeding or duplicate and realize, infect being meant respiratory tract infection, digestive tract infection, reproductive tract infection or systemic infection in the described cell that causes by spirillum.
2, purposes as claimed in claim 1 is characterized in that, the medicine that infects in the described inhibition cell is the oral preparations that 4-removes dimethylamino fairy ring element.
3, purposes as claimed in claim 1 is characterized in that, the medicine that infects in the described inhibition cell is the external preparation that 4-removes dimethylamino fairy ring element.
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