CN102631356B - Application of 4-dedimethyl tetracycline derivatives in aspect of resisting Helicobacter pylori - Google Patents
Application of 4-dedimethyl tetracycline derivatives in aspect of resisting Helicobacter pylori Download PDFInfo
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Abstract
The invention discloses an application of 4-dedimethyl tetracycline and/or 4-dedimethyl tetracycline derivatives in preparing a medicine for treating diseases inflected by Helicobacter pylori and disinfecting medical equipment. The invention further provides a medicine for treating diseases inflected by Helicobacter pylori, and the medicine can be manufactured into tablets, capsules, soft paste, lotions and aerosols. The 4-dedimethyl tetracycline and/or 4-dedimethyl tetracycline derivatives have no resistance to medicines, and the functions of resisting the Helicobacter pylori, inflammation and metalloprotease of the medicine can be utilized to alleviate or cure gastritis inflected by the Helicobacter pylori and other diseases inflected by the Helicobacter pylori.
Description
Technical field
The present invention relates to 4-dedimethylamino tetracycline derivant at purposes and the resulting pharmaceutical composition prepared aspect medicine for anti Helicobacter pylori; The invention still further relates to the purposes of 4-dedimethylamino tetracycline derivant aspect preparation medicine that medical apparatus and instruments is carried out disinfection.
Background technology
Tetracycline (Tetracyclines) is the antimicrobial drug that a class is produced by antibacterial Streptomyces aureofaciens, and main antibacterial action is the protein synthesis by anti-bacteria.Its bacteriostasis mechanism is: tetracycline molecule enters the small subunit (being 30S subunit) that is attached to bacterial ribosome in antibacterial, identification and pairing between the anticodon of aminoacyl-tRNA and the codon of mRNA have directly been affected, thereby stop the protein synthesis in antibacterial, cause the antibacterial breeding that stops growing.Under immune system effect in human body, 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 bacterial cell target structure institute necessary.
Each group on tetracycline parent nucleus has different contributions to antibacterial action, wherein with 4-dimethylamino (the 4th-N (CH
3)
2having the greatest impact group).Studies have shown that of past, the tetracycline molecule (that is: 4-dedimethylamino tetracycline) of removing 4-dimethylamino loses more than 90% antibacterium ability.
The hydrophilic effect having due to 4-dimethylamino, thus make 4-dedimethylamino tetracycline derivant fat-soluble (or vegetables aqueous) compare remarkable increase with tetracycline, also increased their ability that enters cell (consulting Fig. 1 and Biao 1-2) simultaneously.For example, compare with tetracycline, 4-dedimethylamino sancycline (4-dedimethylamino sancycline) loses dimethylamino (hydrophilic group) and the 6th the 4th of parent nucleus and loses hydroxyl (hydrophilic group) and methyl, all increases (consulting table 2) greatly of ability that it is fat-soluble and enter cell, this is the important feature that this medicine enters cells play effect.The antifungic action of recent findings 4-dedimethylamino tetracycline derivant may be 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, for example, the chitin of fungus (Chitin) has important effect in fungal cell wall function, and the impact that medicine is entered to fungal cell is very large.Research also finds, 4-dedimethylamino tetracycline derivant can enter fungal cell in a large number, its antifungic action be likely by conjunction with and suppress intracellular organelle (as mitochondrion etc.) and the function of some enzyme is achieved.
4-dedimethylamino tetracycline derivant also has an important biological action, the i.e. inhibitory action to metalloproteases (Metalloproteinase, MP).This analog derivative is extensively thought to have antiinflammatory action to the inhibition of MP, because the metalloproteases that host cell and pathogen (as antibacterial) discharge in inflammation (as Collagenase etc.) to the Degradation of inflammation histone, be the key factor that causes disorganization and pathogen diffusion.Meanwhile, some metalloproteases be also some interleukins (as TNF--the key factor that α) generates and discharge.
Helicobacter pylori (Helicobacter Pylori, HP) first found in nineteen eighty-two by Barry Marshall (Barry J.Marshall) and guest sieve Warren (J.Robin Warren), and therefore they obtain Nobel physiology or the Medicine of 2005.HP is the antibacterial of a kind of one pole, many flagellums, the blunt circle of end, helically bent.On gastric epithelial cell surface, be often typical helical form or arc, but while growing, can occur shaft-like or spherical shape on solid medium.HP is microaerobe, under atmosphere or absolute anaerobic environment, can not grow.The medical significance of helicobacter pylori is, its infection can cause the main pathogenic of chronic active gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma and gastric cancer, therefore, 1994 World Health Organization (WHO)/international cancer research institution (WHO/IARC) HP is decided to be to the carcinogenic pathogen of I class.
HP is the most commonly encountered diseases substance that causes gastritis.Under normal circumstances, coat of the stomach has a series of perfect self-protective mechanisms (secretory function of gastric acid, protease etc.), can resist per os and the microbiological attack that enters.Yet HP but can break through this natural cover for defense of coat of the stomach easily, its reason mainly contains: (1) makes HP penetrate the factor that rete malpighii is settled down on gastric epithelial cell surface; (2) the toxin factor to destructions such as gastric epithelial cells; (3) various inflammatory cells and inflammatory mediator; (4) immune-reactive substance etc.These factors cause the basic pathology that HP infects to change just, comprise various types of acute and chronic gastritis.
HP infects has also increased the danger that duodenum and gastric ulcer occur widely.According to statistics, may there is peptic ulcer disease in about 17%HP infected patient.Simultaneously, treat clinically HP and infect the healing that can accelerate ulcer and the relapse rate that reduces ulcer, only by anti-HP Drug therapy, also can effectively cure gastric duodenal ulcer, show that HP infects the reason that has become some Gastrointestinal ulcers, these discoveries are also proven in zoopery.
The most important thing is, HP is found there is substantial connection with generation and the development of gastric cancer.According to the experimental results at present HP being infected, people have proposed to cause about HP several mechanisms of gastric cancer, comprising: the metabolite of (1) HP directly transforms gastric mucosal cell; (2) similar Viral Carcinogenesis mechanism, some DNA fragmentation of HP is integrated directly into host cell gene group, causes cell transformation; (3) HP causes the inflammatory reaction of cell, causes genotoxicity effect.
Epidemiological study shows in world wide, approximately have more than 50% population to infect HP, and its sickness rate is also different, even also not identical in each area of same country at every country.In Asia, the teenager of the states such as inland of China, Hong-Kong, Vietnam, India infects HP probability and is respectively 60%, 50%, 40%, 70%.In the Gastric Biopsy of Patients with Chronic Gastritis, the recall rate of HP can reach 80%～90%, and Peptic Ulcers is higher, can reach more than 95%.Gastric cancer is the local epithelial cell generation alienation due to stomach, so recall rate is just reported and differed.
The anti-HP medicine of commonly using both at home and abroad at present has WEIFUCHUN PIAN, amoxicillin, metronidazole, clarithromycin, tetracycline, doxycycline, furazolidone, organic colloidal state bismuth, veytalo tablet, the easypro equality of Xi Pishi powder stomach function regulating.But these antibiotics that infect due to treatment HP are widely used, cause HP to produce drug resistance problem to these medicines, this is to cause the HP of some patients were to infect the major reason that can not effect a radical cure.Therefore, at present clinically in the urgent need to the medicine of replaceability.
Summary of the invention
For existing anti-HP technical deficiency, the object of this invention is to provide effectively a kind of and not yet cause that HP produces novel anti-HP medicine and the application thereof of drug resistance.
Object of the present invention realizes by following technical scheme: adopt 4-dedimethylamino tetracycline derivant, it can prepare the medicine of anti-helicobacter pylori; Wherein, 4-dedimethylamino tetracycline derivant has following molecular characterization: its dimethylamino of the 4th in tetracycline parent nucleus is removed, these 4-dedimethylamino tetracycline derivants can be carried out synthetic and obtain through chemical synthesis process, also can pass through semisynthesis, the 4th dimethylamino of different tetracycline compounds removed and formed; Or obtain by known enzymatic or non-enzymatic chemical modification method.In addition, other locational group of the tetracycline parent nucleus of 4-dedimethylamino tetracycline derivant also can be replaced by different groups or atom by chemical modification technology.
4-dedimethylamino tetracycline derivant of the present invention has the molecular structure shown in Fig. 1 and table 2.
Preferably, 4-dedimethylamino tetracycline derivant of the present invention can be for being selected from as one or more in material of next group: 4-dedimethylamino tetracycline (4-dedimethylamino tetracycline), 4-dedimethylamino sancycline (4-dedimethylamino sancycline, or claim: 4-dedimethylamino sancycline), 4-dedimethylamino chlorotetracycline (4-dedimethylamino chlorotetracycline), 4-dedimethylamino oxytetracycline (4-dedimethylamino oxytetracycline), 4-goes dimethylamino to think much and encircles element (4-dedimethylamino doxycycline, or claim: CMT-8), 4-removes the little ring element of dimethylamino (4-dedimethylamino minocycline) etc., and the chemical modification object at other position of these 4-dedimethylamino tetracycline derivants, comprise the 2nd and the chemical modification object of 9.
In the present invention, the chemical modification object at other position of 4-dedimethylamino tetracycline derivant is to be selected from as one or more in material of next group: 2-methyl-4-dedimethylamino tetracycline (2-methyl-4-dedimethylamino tetracycline), 2-methylol-4-dedimethylamino tetracycline (2-hydroxymethyl-4-dedimethylamino tetracycline), 2-pyrroles's methyl-4-dedimethylamino tetracycline (2-N-pyrrolidinomethyl-4-dedimethylamino tetracycline), 4-removes the amino fairy ring element of dimethylamino-9-((4-dedimethylamino-9-amino sancycline), 4-goes dimethylamino-9-amino to think much and encircles (referring to table 1) such as elements (4-dedimethylamino-9-amino doxycycline).
The medicine of anti-helicobacter pylori of the present invention can be for comprising the external used medicine of 4-dedimethylamino tetracycline derivant, also can be for comprising the injecting drug use of 4-dedimethylamino tetracycline derivant, or the endo-medicine for comprising 4-dedimethylamino tetracycline derivant.
On the other hand, in order to realize object of the present invention, the present invention also provides a kind of pharmaceutical composition of anti-helicobacter pylori, and it comprises 4-dedimethylamino tetracycline derivant and the physiologically acceptable pharmaceutical carrier of effective dose.This pharmaceutical composition can adopt the dosage form of tablet, capsule, ointment, varnish, aerosol.
For example, when this pharmaceutical composition is external used medicine, the effective dose of 4-dedimethylamino tetracycline derivant (percentage by weight) can be 0.01～5%, emulsifying agent 0.0001～0.5%, water 94.5～99.99%; When this pharmaceutical composition is endo-medicine, its effective dose (percentage by weight) can 90～99%, sugar-coat 1～10%; When this pharmaceutical composition is injection, it can be: its effective dose (percentage by weight) 0.1～10% of a., sodium chloride 0.9～1%, water 89～99%; Or its effective dose (percentage by weight) 0.1～10% of b., glucose 5～10%, water 80～94.9%; Or its effective dose (percentage by weight) 0.1～10% of c., sodium chloride 0.9～1%, glucose 5～10%, water 79～94%.
Again on the one hand, in order to realize object of the present invention, the present invention also provides the purposes aspect the medicine that 4-dedimethylamino tetracycline derivant carries out disinfection to medical apparatus and instruments in preparation.Wherein, 4-dedimethylamino tetracycline derivant is to be selected from as one or more in material of next group: 4-dedimethylamino tetracycline, 4-dedimethylamino sancycline, 4-dedimethylamino chlorotetracycline, 4-dedimethylamino oxytetracycline, 4-go think much ring element, 4-of dimethylamino to remove the chemical modification object at other position of the little ring element of dimethylamino and these 4-dedimethylamino tetracycline derivants.
Sea of the present invention provides a kind of Pharmaceutical composition for medical apparatus sterilizing, 4-dedimethylamino tetracycline derivant and pharmaceutical carrier that it contains effective dose.
By being carried out to external anti Helicobacter pylori activity, 4-dedimethylamino tetracycline derivant of the present invention tests, prove that it has significant anti Helicobacter pylori activity, can be applied to prepare the external disinfecting drug of anti-helicobacter pylori completely, comprise the disinfecting drug (in Table 3) of medical apparatus and instruments.
By the anti Helicobacter pylori activity that 4-dedimethylamino tetracycline derivant of the present invention is carried out in Mice Body, test, prove that it has the effect of significant anti-HP infected gastritis, can be applied to prepare the medicine for anti Helicobacter pylori of for oral administration or external completely, comprise the treatment gastritis that causes of helicobacter pylori and the medicine (in Table 4, Fig. 3-4) of digestive tract ulcer.
Because the infection of helicobacter pylori has been proved to be one of important paathogenic factor of gastric cancer, therefore, 4-dedimethylamino tetracycline derivant of the present invention reduces the incidence rate of gastric cancer by the helicobacter pylori in elimination digestive tract, have the function of prevention gastric cancer.
4-dedimethylamino tetracycline derivant also has an important biological action, the i.e. inhibitory action to metalloproteases (Metalloproteinase, MP).This analog derivative is extensively thought to have antiinflammatory action to the inhibition of MP, because the metalloproteases that host cell and pathogen (as antibacterial) discharge in inflammation (as Collagenase etc.) to the Degradation of inflammation histone, be the key factor that causes disorganization and pathogen diffusion.Meanwhile, some metalloproteases be also some interleukins (as TNF-) the key factor (see figure 5) that generates and discharge.Therefore, 4-dedimethylamino tetracycline derivant increases the effect of its treatment Helicobacter pylori infection and anti-cancer by its antiinflammatory action.
Accompanying drawing explanation
Fig. 1 is the structural formula that tetracycline and several 4-go dimethylamino derivant: (a) structure of tetracycline molecule; (b) tetracycline; (c) 4-dedimethylamino sancycline; (d) 4-dedimethylamino tetracycline;
Fig. 2 is laser electron-microscope scanning collection of illustrative plates, shows that 4-dedimethylamino sancycline enters person monocytic cell in a large number, proves that the penetration power of its cell membrane is strong;
Fig. 3 be 4-dedimethylamino sancycline to the treatment of mice HP infectious gastritis after gastric tissue section.The gastric mucosa surface that shows treatment group heals obviously and the gastric mucosa surface badly broken of HP infection matched group, leukocyte infiltration, and inflammatory reaction is obvious, proves that this medicine has significant therapeutic effect to mice HP infectious gastritis;
Fig. 4 is the Microscopic observation of 4-dedimethylamino sancycline to the treatment experiment of mice HP infectious gastritis, and the size of demonstration treatment group stomach and mucosa are tending towards stomach enlargement, mucosa normal and HP infection matched group and are subject to major injury;
Fig. 5 is that 4-dedimethylamino sancycline stimulates the inhibitory action of lower person monocytic cell's release tumor necrosis factor (TNF-α) and il-1 (IL-11 β) to lipopolysaccharide (LPS), proves that this medicine has anti-inflammatory properties.Dxy is the ring element of thinking much; Cx is the tetracycline derivant of unknown structure.
The specific embodiment
Embodiment 1
During medicine for external use, 4-dedimethylamino sancycline contains effective dose 0.01%, fat-soluble medium vaseline 99.99%, and common process is made external and is reached the effect that anti-HP infects.
Embodiment 2
During medicine for external use, 4-dedimethylamino sancycline contains effective dose 5%, fat-soluble medium tristerin 95%, and common process is made external and is reached the effect that anti-HP infects.
Embodiment 3
During medicine for external use, 4-dedimethylamino chlorotetracycline contains effective dose 0.05%, fat-soluble medium sodium laurylsulfate 99.95%, and common process is made external and is reached the effect that anti-HP infects.
Embodiment 4
During medicine for external use, 4-dedimethylamino sancycline contains effective dose 1%, fat-soluble medium white vaseline 99%, and common process is made external and is reached the effect that anti-HP infects.
Embodiment 5
During medicine for external use, 4-dedimethylamino chlorotetracycline contains effective dose 2%, fat-soluble medium pyrene Oleum Sesami 98%, and common process is made external and is reached the effect that anti-HP infects.
Embodiment 6
During medicine for external use, 4-dedimethylamino sancycline contains effective dose 3%, the liquid paraffin wax 97% of fat-soluble medium, and common process is made external and is reached the effect that anti-HP infects.
Embodiment 7
During medicine for external use, 4-dedimethylamino chlorotetracycline contains effective dose 4%, fat-soluble medium lanoline 96%, and common process is made external and is reached the effect that anti-HP infects.
Embodiment 8
During medicine for external use, 4-dedimethylamino sancycline contains effective dose 2.5%, fat-soluble medium sodium laurylsulfate 97.5%, and common process is made external and is reached the effect that anti-HP infects.
Embodiment 9
During external HP disinfectant, 4-dedimethylamino sancycline contains effective dose 0.0001%, emulsifying agent 0.0001%, and water 99.9998%, common process is made the effect that disinfectant for external use reaches HP deactivation.
Embodiment 10
During external HP disinfectant, 4-dedimethylamino sancycline contains effective dose 0.001%, emulsifying agent 0.0001%, and water 99.9989%, common process is made the effect that disinfectant for external use reaches HP deactivation.
Embodiment 11
During external HP disinfectant, 4-dedimethylamino chlorotetracycline contains effective dose 0.01%, emulsifying agent 0.0001%, and water 99.9899%, common process is made the effect that disinfectant for external use reaches HP deactivation.
Embodiment 12
During oral medicine, 4-dedimethylamino sancycline is 90% containing effective dose, sugar-coat 10%, and common process is made, and takes and reaches the effect that anti-HP infects.
Embodiment 13
During oral medicine, 4-dedimethylamino sancycline is 99% containing effective dose, sugar-coat 1%, and common process is made, and takes and reaches the effect that anti-HP infects.
Embodiment 14
During injecting drug use, 4-dedimethylamino sancycline contains effective dose 0.1%, sodium chloride 1%, and water 98.9%, common process is made, and reaches the effect that anti-HP infects after injection.
Embodiment 15
During injecting drug use, 4-dedimethylamino sancycline contains effective dose 10%, sodium chloride 0.9%, and water 89.1%, common process is made, and reaches the effect that anti-HP infects after injection.
Embodiment 16
During injecting drug use, 4-dedimethylamino sancycline contains effective dose 0.1%, glucose 10%, and water 89.9%, common process is made, and reaches the effect that anti-HP infects after injection.
Embodiment 17
During injecting drug use, 4-dedimethylamino sancycline contains effective dose 10%, glucose 5%, and water 85%, common process is made, and reaches the effect that anti-HP infects after injection.
Embodiment 18
During injecting drug use, 4-dedimethylamino sancycline contains effective dose 0.1%, sodium chloride 1%, and glucose 10%, water 88.9%, common process is made, and reaches the effect that HP infects after injection.
Embodiment 19
During injecting drug use, 4-dedimethylamino sancycline contains effective dose 10%, sodium chloride 1%, and glucose 10%, water 79%, common process is made, and reaches the effect that anti-HP infects after injection.
In embodiment 1～19, verify that 4-dedimethylamino tetracycline derivant can suppress the effect of HP, the HP urase that can make biopsy detects, or serum HP antibody test, or HP cultivates detection.
Table 1 is that some tetracyclines and 4-thereof go the important group of dimethylamino derivant to distribute; Table 2 item is the fat-soluble of 4-dedimethylamino tetracycline derivant and the testing result that enters person monocytic cell; Table 3 is 4-dedimethylamino sancycline and the external MIC measurement result of 4-dedimethylamino chlorotetracycline to two kinds of HP bacterial strains; Table 4 is level determinations of IL-1 in gastric mucosa HP urase testing result and serum after 4-dedimethylamino sancycline treatment mice HP infectious gastritis.
The laser electron-microscope scanning collection of illustrative plates of Fig. 2 shows, after 4-dedimethylamino sancycline and person monocytic cell's suspension are incubated 2 hours, is found to enter in a large number in cell (fluorescence in cell is produced by this medicine), proves that the penetration power of its cell membrane is strong.Fig. 4 is the Microscopic observation of 4-dedimethylamino sancycline to the treatment experiment of mice HP infectious gastritis, and wherein, " Normal group " infects without HP, and visible ruga gastrica texture is thinner; " HP infects matched group " infects but without Drug therapy, sees the whole inflammation swelling of stomach for HP, and ruga gastrica texture is thick; " HP infects medication group " carries out 4-dedimethylamino sancycline gavage after HP infects, and 2mg/Kg/ day, continuous 7 days, sees that the size of stomach and texture approach " Normal group "; Proof 4-dedimethylamino sancycline has therapeutic effect to HP infectious gastritis.Fig. 3 be 4-dedimethylamino sancycline to the treatment of mice HP infectious gastritis after gastric tissue section, " Normal group " visible gastric mucosa surface is neat; " HP infects matched group " sees that gastric mucosa surface is damaged, leukocyte infiltration, and inflammatory reaction is obvious; " HP infects medication group " sees gastric mucosa surface healing obviously.Fig. 5 is that 4-dedimethylamino sancycline stimulates the inhibitory action of lower person monocytic cell's release tumor necrosis factor (TNF-α) and il-1 (IL-11 β) to lipopolysaccharide (LPS), proves that this medicine has anti-inflammatory properties.
Table 1
Table 2
* Cx: unknown structure tetracycline derivant.
Table 3*
* this detection entrusts Shanghai The National Center for Drug Screening to complete.
Table 4
Claims (4)
1.4-goes the purposes of dimethylamino tetracycline derivant aspect the medicine of the anti-helicobacter pylori of preparation, wherein, described 4-dedimethylamino tetracycline derivant is to be selected from as one or more in material of next group: 4-dedimethylamino sancycline and 4-dedimethylamino chlorotetracycline.
2. purposes as claimed in claim 1, wherein, described medicine is the external used medicine that comprises 4-dedimethylamino tetracycline derivant.
3. purposes as claimed in claim 1, wherein, described medicine is the injecting drug use that comprises 4-dedimethylamino tetracycline derivant.
4. purposes as claimed in claim 1, wherein, described medicine is the endo-medicine that comprises 4-dedimethylamino tetracycline derivant.
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| US3029284A (en) * | 1960-09-14 | 1962-04-10 | Pfizer & Co C | Nu-dealkylation of carboxamido-nu-alkyltetracycline and its analogs |
| US5122519A (en) * | 1989-06-27 | 1992-06-16 | American Cyanamid Company | Stable, cosmetically acceptable topical gel formulation and method of treatment for acne |
| US6506740B1 (en) * | 1998-11-18 | 2003-01-14 | Robert A. Ashley | 4-dedimethylaminotetracycline derivatives |
| JP2005505588A (en) * | 2001-10-05 | 2005-02-24 | テトラジェネックス ファーマスーティカルズ インク | Tetracycline derivative and method of using the same |
| CN100493513C (en) * | 2003-06-23 | 2009-06-03 | 刘誉 | Application of 4-de-dimethyltetracycline derivative |
| CN1608625A (en) * | 2003-10-23 | 2005-04-27 | 刘誉 | Use and medicine of 4-dedimethylamino tetracycline and its derivative in treating skin diseases |
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