CN106902116A - A kind of new opplication of rifamycin quinolizine ketone dual-target molecule - Google Patents
A kind of new opplication of rifamycin quinolizine ketone dual-target molecule Download PDFInfo
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- CN106902116A CN106902116A CN201710110007.2A CN201710110007A CN106902116A CN 106902116 A CN106902116 A CN 106902116A CN 201710110007 A CN201710110007 A CN 201710110007A CN 106902116 A CN106902116 A CN 106902116A
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- bacterium
- rifamycin
- target molecule
- bacteroides
- quinolizine ketone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
Abstract
Present invention is disclosed application of the rifamycin quinolizine ketone dual-target molecule shown in a kind of formula I in anaerobic bacteria flora is suppressed.The rifamycin quinolizine ketone dual-target molecule of formula I has broad spectrum antibiotic activity, including active to the anaerobic bacteria including most vaginal pathogenics, its antibacterial activity in vitro is better than the line bacteria resistance vagina medicine of metronidazole and clindamycin etc., has good application prospect to the prevention and treatment aspect of the microbial bacterial vaginosis BV of anaerobism or other relevant diseases.
Description
Technical field
The invention belongs to medicinal chemistry arts, more particularly to a kind of rifamycin-quinolizine ketone dual-target molecule new opplication.
Background technology
Anaerobic bacteria (anaerobic bacteria) is a class better than being grown in aerobic environment under anaerobic, without
Can be in the bacterium of the solid medium superficial growth under air (18% oxygen) and (or) 10% gas concentration lwevel.This kind of bacterium
Lack complete metabolism enzyme system, its energetic supersession is carried out in the way of anaerobic fermentation.
Anaerobic bacteria includes following several classes：
1st, gram-positive anaerobic cocci (Gram-positive anaerobic cocci, GPAC)
Including peptostreptococcus (Peptostreptococcus), micro- monad (Finegoldia), anaerobic cocci
(Anaerococcus), thermophilic peptone bacterium (Peptoniphilus), Wei Yong Shi coccuses (Veillonella) etc., be human mouth, on exhale
A part for road, intestines and stomach and female genitourinary system microorganism species is inhaled, is conditioned pathogen, non-human each portion can be caused
Different degrees of infection (accounting for the 25-30% of whole anaerobic infections), including mild skin is divided to suppurate or serious brain and dura mater
Outer abscess, bacteremia, endocarditis, necrotizing pneumonia and dense toxicity are miscarried.Pleura/pulmonary infection that GPAC is caused reaches
40%, in the infection of its serious wounds for causing, the death rate may be up to 75%.GAPC can also cause eye, face and head, neck sense
Dye, meningitis, heart Zhou Yan, stock and joint (including joint prosthesis) infect, galactapostema, urinary tract infection etc..
2nd, Gram-negative anaerobic cocci (Gram-negative anaerobic cocci, GNPC)
GNPC is human mouth, genitourinary tract, one of respiratory tract and normal intestinal flora, and proportion is very low in clinical sample,
But there is increase trend.
3rd, non-sporogenesis Gram-positive anaerobic bacillus(cillus anaerobicus) (Non-spore-forming anaerobic Gram-
positive rods)
Including Propionibacterium (Propionibacterium), Bacillus acidi lactici (Lactobacillus), actinomyces
(Actinomyces), eubacteria (Eubacterium), Ai Gete bacterium (Eggerthella), atropic ripple bacterium (Atopobium),
Bifidobacterium (Bifidobactrium), Mobiluncus (Mobiluncus) etc..Compound infection mostly related to mucous membrane, mouth
Chamber and excrement are main infection sources.The major reason of postoperative death rate and the incidence of disease.
4th, Gram-negative anaerobic bacillus(cillus anaerobicus) (Anaerobic Gram-negative rods)
Including bacteroid (Bacteroides), Detection of Porphyromonas (Porphyromonas), Prey irrigates bacterium
(Prevotella), fusiform bacilarmature (Fusobacterium) etc., main parasitic is in human mouth, intestines and stomach and vagina mucosa, infection
Normally due to mucous membrane is impaired causing, such as vaginitis and periodontitis.
5th, sporogenesis Gram-positive anaerobic bacillus(cillus anaerobicus) (Spore-forming Gram-positive rods)
Including Clostridium (Clostridium), clostruidium bacteremia can be caused, poisoned by food, it is bad
Dead property enteritis, iatrogenic diarrhoea (CDI), antibiotic correlation pseudomembranous colitis, skin and soft tissue infection etc..
Bacterial vaginosis BV (Bacterial Vaginosis, BV) is the common LGTI of Female in child bearing period
Disease, is the synthesis that a kind of absence of vagina mucosal inflammation performance for causing that changes is constituted due to normal vagina Tiny ecosystem flora
Levy.The whole world there are about millions of women and suffers from bacterial vaginosis BV every year, have a strong impact on female reproductive health.BV can trigger not
Good pregnancy outcome, such as spontaneous abortion, premature labor, amniotic fluid infection, puerperal endometritis and cesarean section infection and peri-natal infant are simultaneously
Hair disease etc..Additionally, the recurrence and persistent infection of BV can also increase trichomonal vaginitis, VVC, cervical carcinoma
The risk infected with human immunodeficiency virus (human immunodeficiency virus, HIV).
Gardnerella vaginalis (Gardnerella Vaginalis, GV) are one of primary pathogenic events of BV, and metronidazole is still
It is the fiest-tire medication of the routine clinical treatments of current BV, although can reach 70%~80% to the short-term cure rate of BV, and 3 months
Interior recurrence rate but may be up to 58%.The presence of metronidazole antibody-resistant bacterium and the formation of biomembrane of GV are probably that BV recurs and controls
Treat the major reason of failure.There are some researches show the reaction of the bacteria medicine in biomembrane exists with its planktonic growth mode
Significant difference, may be relevant with the penetration power that growth conditions of the bacterium in biomembrane and biomembrane reduce antibacterials.Cause
This, the new focus for being the discovery that BV recurrences and resistance research of the biofilm structure of Gardnerella generation.
At present, Chinese patent ZL200580031655.4 " Ryfamycin derivative for the treatment of microorganism infection " disclosing
Compound (R) -3- [(4- 1- [1- (the fluoro- 9- methyl -4- oxos -4H- quinolizines -8- bases of 3- carboxyl -1- cyclopropyl -7-)-pyrrolidines -
3- bases-cyclopropyl]-methylamino }-piperidin-1-yl imino group)-methylene]-Rifamycin Sodium, the compound is to Gram-positive
The various bacteria such as bacterium and Escherichia coli has antimicrobial acivity, but is not documented it to anaerobic bacteria flora with anti-
Bacterium activity.
The content of the invention
In view of the defect that above-mentioned prior art is present, the purpose of the present invention is to propose to a kind of double targets of rifamycin-quinolizine ketone
The new opplication of molecule is marked, can effectively suppress anaerobic bacteria flora, can be used in treating bacterial vaginosis BV.
The purpose of the present invention will be achieved by the following technical programs：
The application of rifamycin-quinolizine ketone dual-target molecule shown in a kind of formula I in anaerobic bacteria is suppressed；
Formula I.
Preferably, in above-mentioned application, the anaerobic bacteria flora includes actinomyces naeslundii (Actinomyces
Naeslundii), Pu Shi anaerobic coccis (Anaerococcus prevotii), atropic ripple vagina bacterium (Atopobium
Vaginae), bacteroides fragilis (Bacteroides fragilis) (including metronidazole drug-resistant type), bacteroides thetaiotaomicron
(Bacteroides thetaiotaomicron) (including metronidazole drug-resistant type), Bacteroides gracilis (Bacteroides
Gracilis), bacteroides uniformis (Bacteroides uniformis), bacteroides vulgatus (Bacteroides vulgatus),
Bacteroides ovatus (Bacteroides ovatus) (including metronidazole drug-resistant type), bifidobacterium breve (Bifidobacterium
Breve), bifidobacterium longum (Bifidobacterium longum), clostridium sporogenes (Clostridium
Sporogenes), clostridium perfringens (Clostridium perfringens) (including metronidazole drug-resistant type),
Eubacterium rectale (Eubacterium rectale), karyosome fusiform bacilarmature (Fusobacterium nucleatum), vagina add
Moral receives bacterium (Gardnerella vaginalis), Lactobacillus crispatus (Lactobacillus crispatus), Lactobacillus gasseri
(Lactobacillus gasseri), Lactobacillus Jensenii (Lactobacillus jensenii), Mobiluncus curtisii
(Mobiluncus (curtisii subsp.curtisii)), Mobiluncus mulieris (Mobiluncus mulieris), digestion
Coccus (Peptococcus), sugared thermophilic peptone bacterium (Peptoniphilus asaccharolyticus) (including metronidazole resistance is not understood
Type), peptostreptococcus magnus (Peptostreptococcus), peptostreptococcus anaerobius (Peptostreptococcus
Anaerobius), the fertile bacterium of the sugared peptone Prey of two Lu Puleiwo bacterium (Prevotella bivia) (including metronidazole drug-resistant type), solution
(Prevotella disiens), middle Prey fertile bacterium (Prevotella intermedia), treponema denticola
One or more in (Treponema denticola) and little Wei Yong Shi coccuses (Veionella parvula) of combination.
The present invention also provides above-mentioned rifamycin-quinolizine ketone dual-target molecule and is lost by anaerobic bacteria flora as preparation treatment
Application in the medicine of the bacterial vaginosis BV (Bacterial Vaginosis, BV) for having regulated and guided.
Preferably, in above-mentioned application, the human body effective dose of the rifamycin-quinolizine ketone dual-target molecule is daily
10 milligrams to 10 grams, treatment cycle is 1-15 days.
Preferably, in above-mentioned application, the administering mode that the application is used is including in drug administration by injection, oral administration, chamber
The combination of one or more in administration, enteral administration and Transdermal absorption.
Preferably, in above-mentioned application, the used form of administration of the application includes injection, suppository, tablet, capsule
The combination of one or more in agent, patch and sustained release agent.
Prominent effect of the invention is：There is the rifamycin of formula I-quinolizine ketone dual-target molecule broad-spectrum antiseptic to live
Property, including active to the anaerobic bacteria including most vaginal pathogenics, its antibacterial activity in vitro be better than metronidazole and gram
The anti-BV medicines of the line of woods mycin etc., to prevention and the treatment aspect of the microbial bacterial vaginosis BV of anaerobism and other relevant diseases
With good application prospect.
Hereinafter specific embodiment of the invention is described in further detail in conjunction with the embodiments just, so that the technology of the present invention side
Case is more readily understood, grasps.
Specific embodiment
The method of the present invention is illustrated below by specific embodiment, but the invention is not limited in this.Following realities
Experimental technique described in example is applied, unless otherwise specified, conventional method is；The reagent and material, unless otherwise specified,
Obtain from commercial channels.
Embodiment 1
The present embodiment provide formula I shown in rifamycin-quinolizine ketone dual-target molecule suppress anaerobic bacteria in application；
Wherein, anaerobic bacteria include actinomyces naeslundii, Pu Shi anaerobic coccis, atropic ripple vagina bacterium, bacteroides fragilis (including
Metronidazole drug-resistant type), bacteroides thetaiotaomicron (including metronidazole drug-resistant type), Bacteroides gracilis, bacteroides uniformis, bacteroides vulgatus,
Bacteroides ovatus (including metronidazole drug-resistant type), bifidobacterium breve, bifidobacterium longum, clostridium sporogenes, aerogenesis pod
Film clostruidium (including metronidazole drug-resistant type), Eubacterium rectale, karyosome fusiform bacilarmature, gardnerella vaginalis, curling breast
Bacillus, Lactobacillus gasseri, Lactobacillus Jensenii, Mobiluncus curtisii, Mobiluncus mulieris, peptococcus (Niger), puzzled sugar
Thermophilic peptone bacterium (including metronidazole drug-resistant type), peptostreptococcus magnus, peptostreptococcus anaerobius, two Lu Puleiwo bacterium (including metronidazole
Drug-resistant type), the fertile bacterium of the sugared peptone Prey of solution, one or more in middle Prey fertile bacterium, treponema denticola and little Wei Yong Shi coccuses
Combination.
In the present embodiment, rifamycin-quinolizine ketone dual-target molecule shown in formula I disease related to bacterial vaginosis BV
Opportunistic pathogen has done test experience, and pathogen includes above-mentioned anaerobic bacteria.Test is used and clinical and laboratory standard research institute
(Clinical and Laboratory Standards Institute,CLSI；The consistent agar dilution of guide 1-3).
Test is carried out under anaerobic.Control group compound is metronidazole, the sharp gentle clindamycins of Fu.
Material and method
Test compound
There is provided by Dan Nuo Pharmaceuticals Ltds, in -20 degrees Celsius of preservations before detection.Three kinds of control drugs are provided by Sigma.
All mother liquors it is automatic it is degerming before place at least 1 hour.
Test strain
The clinical separation strain of detection is from Unite States Standard DSMZ (American Type Culture
Collection, ATCC, Manassas, VA) reference bacterium.After receiving bacterial strain, they are inoculated with respectively and suitable agar plate
On be placed in optimization under conditions of grow.Being cloned in of growing is made bacterial suspension in the nutrient solution containing cryoprotector
Liquid, in -80 degrees Celsius of freezen protectives after packing.Before test, by the microbionation of freezing to suitable agar ware and growth is cultivated.
Anaerobic bacteria is in 35 degrees Celsius of growths 48 are small in Bactron II anaerobics cabinet (Shel Lab, Cornelius, OR) before testing
When.
Test media
Culture medium for the detection of Anaerobic Agar dilution method susceptibility is supplement Brucella agar (SBA), by micro- containing 5
Hemin (the BD/BBL of grams per milliliter；Article No.：5300551), vitamin K1 (Sigma, St.Louis, the MO of 1 mcg/ml；
Article No. SLBC4685V) and 5% color lake Sheep Blood (Cleveland Scientific, Bath, OH, article No. 291958)
Brucella agar.
The preparation and storage of all of above culture medium are carried out according to CLSI (1-3).
Agar dilution determines minimum inhibitory concentration (Minimum Inhibitory Concentrations, MIC)
The MIC value of all microorganisms in addition to hemophilus is determined using the agar dilution (1-2) in CLSI.According to
CLSI guides (1-2) carry out drug dilution and prepare the agar plate of drug containing by hand.To dry agar surface, porous plate is existed
Room temperature is placed 1 hour.Will be used for anaerobic condition under test agar plate preset about 1 hour in anaerobic cabinet.With nephometer (Dade
Behring MicroScan, Wet Sacramento, CA) each separation strains are adjusted to 0.5 Mike in suitable culture medium
Fa Lanshi turbidity standards.Then each bacterial suspension is transferred in the hole of detection plate with stainless steel reproducer.Greatly containing about 10
(5)/1-2 microlitres of microbionation is put into anaerobic cabinet after drying to the agar surface per hole by medicine plate and without medicine control board
35 degrees Celsius of anaerobic environment is fed 42-48 hours.Determine MIC (1-2) according to CLSI guides after culture.
Test result is as shown in table 1 below.
Table 1
From above-mentioned test result, rifamycin-quinolizine ketone dual-target molecule (formula I) in addition to a small number of bacterial strains, to exhausted
The In Vitro Bacteriostatic (MIC) of most of anaerobic bacteria is higher than metronidazole, and 100 times of metronidazole are up to some bacterial strain antibacterial activities
More than.For common BV dominant bacterias such as gardnerella vaginalis, Prey irrigates bacterium, Mobiluncus, atropic ripple vagina bacterium and digestion hammer
Bacterium has identical or stronger bacteriostatic activity.Lived from the wide spectrum anaerobe resistant of rifamycin-quinolizine ketone dual-target molecule (formula I)
Property can predict that it plants the therapeutic action that the infection that causes of bacteriums also has to other of display activity.
Antibacterial activity in vitro according to rifamycin-quinolizine ketone dual-target molecule (formula I) speculates that its effective dose is first nitre
The 1/100 of azoles effective dose, equivalent to 10 milligrams, in order to further improve curative effect, can further incremental dose to 10 grams, with
Reach its highest effective dose.
Embodiment 2
The present embodiment provides a kind of quick release oral formulations of the rifamycin-quinolizine ketone dual-target molecule shown in formula I
Prescription and preparation method.
Rifamycin-quinolizine ketone dual-target molecule and the auxiliary material shown in formula I are weighed as above-mentioned recipe quantity.By PVP K30
(PVP K30) and lauryl sodium sulfate (SDS), is dissolved in purified water, stirs 1 hour, standby as binder；By formula I
Shown compound, mannitol and carboxyrnethyl starch sodium (DST) cross 30 mesh sieves, add in granulator, premix, impeller mixing speed
700rpm, about 15 minutes time.Again with peristaltic pump with fixed speed (145-165g/ minutes) plus appropriate purified water and bonding
To in granulator mixture, granulator impeller mixing speed 400rpm, about 1~2 minute time, binder is added after finishing for agent,
Continue to mix 0.5~1 minute；Wet granular is dried using fluid bed, if EAT is 60 DEG C, intake 40m3/h；
Weight according to dried dry particl material is calculated and should add silica and magnesium stearate, first by silica and dry particl
Put and mixed in hopper blender, incorporation time 15 minutes；Rotating speed 20rpm；Add magnesium stearate, incorporation time 6 minutes,
Mixing velocity is 20rpm, takes the material after total mixing and surveys using capsule filling machine No. 0 capsule of filling, and the sharp good fortune obtained final product shown in formula I is mould
Element-quinolizine ketone dual-target molecule hard capsule.
Material after total mixing is used into tabletting machine, the rifamycin-quinolizine ketone dual-target molecule piece shown in formula I is obtained final product
Agent.
Embodiment 3
The present embodiment provides a kind of injection preparation method of the rifamycin-quinolizine ketone dual-target molecule shown in formula I.
Under nitrogen protection by mannitol, sodium sulphoxylate acetaldenyde, the appropriate water for injection of Tween-80 addition, the institute of formula I is added
The rifamycin for showing-quinolizine ketone dual-target molecule, moderate-speed mixer 10-15 minutes, the rifamycin-quinolizine ketone shown in moistening type I
Dual-target molecule, 1N NaOH are slowly added dropwise, time-consuming about 175 minutes (preceding fast rear slow), the rifamycin-quinolizine ketone shown in formula I
Dual-target molecule all dissolves, 0.45+0.22 μm of twice filtering with microporous membrane, in the filling vial to 10mL of filtrate, per bottled
3.5mL, vial is freezed in being transferred to freeze dryer, and the rifamycin-quinolizine ketone dual-target point shown in formula I is obtained final product after Zha Gai
The freeze drying powder injection of son.
Embodiment 4
The present embodiment provides a kind of exterior-applied gel preparation side of the rifamycin-quinolizine ketone dual-target molecule shown in formula I
Method.
Carbomer is soaked with ethanol in proper amount, about 1600mL is diluted to purified water under stirring, boiled, continuing stirring makes
Its transparent shape coagulant liquid, cools.Rifamycin shown in modus ponens I-quinolizine ketone dual-target molecule, natural borneol and essence again,
Dissolved with ethanol in adding gelatinous transparent liquid together with surfactant, then 2000mL is settled to purified water, stirred, put
Put more than 12 hours, normal pressure deaeration, packing obtains final product the rifamycin-quinolizine ketone dual-target molecule external application shown in formula I after inspection
Gel.
Claims (6)
1. application of the rifamycin shown in a kind of formula I-quinolizine ketone dual-target molecule in anaerobic bacteria flora is suppressed；
2. application according to claim 1, it is characterised in that the anaerobic bacteria includes actinomyces naeslundii, Pu Shi anaerobism balls
It is bacterium, atropic ripple vagina bacterium, bacteroides fragilis, bacteroides thetaiotaomicron, Bacteroides gracilis, bacteroides uniformis, bacteroides vulgatus, avette
The true bar of bacteroid, bifidobacterium breve, bifidobacterium longum, clostridium sporogenes, clostridium perfringens, rectum
It is bacterium, karyosome fusiform bacilarmature, gardnerella vaginalis, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus Jensenii, Mobiluncus curtisii, shy
Timid Mobiluncus, peptococcus, puzzled sugared thermophilic peptone bacterium, peptostreptococcus magnus, peptostreptococcus anaerobius, two Lu Puleiwo bacterium, solution
Sugared peptone Prey irrigates the combination of one or more in bacterium, middle Prey fertile bacterium, treponema denticola and little Wei Yong Shi coccuses.
3. the rifamycin described in claim 1-quinolizine ketone dual-target molecule is drawn as preparation treatment by vaginal dysbacteriosis
Application in the medicine of the bacterial vaginosis BV for rising.
4. application according to claim 3, it is characterised in that the human body of the rifamycin-quinolizine ketone dual-target molecule
Effective dose is daily 10mg-10g, and treatment cycle is 1-15 days.
5. application according to claim 3, it is characterised in that the administering mode that the application is used include drug administration by injection,
The combination of one or more in oral administration, intracavitary administration, enteral administration and Transdermal absorption.
6. application according to claim 3, it is characterised in that the form of administration that the application is used include injection,
The combination of one or more in suppository, tablet, capsule, patch and sustained release agent.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710110007.2A CN106902116B (en) | 2017-02-28 | 2017-02-28 | Application of rifamycin-quinolizidone dual-target molecule |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710110007.2A CN106902116B (en) | 2017-02-28 | 2017-02-28 | Application of rifamycin-quinolizidone dual-target molecule |
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| CN106902116B CN106902116B (en) | 2021-03-23 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109464673A (en) * | 2019-01-08 | 2019-03-15 | 丹诺医药(苏州）有限公司 | Application and the preparation of rifamycin-quinolizine ketone coupling molecule and its salt |
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| CN101031572A (en) * | 2004-07-22 | 2007-09-05 | 坎布里制药公司 | (r/s) rifamycin derivatives, their preparation and pharmaceutical compositions |
| CN103732212A (en) * | 2011-07-29 | 2014-04-16 | 意大利阿尔法韦士曼制药公司 | Pharmaceutical compositions comprising rifaximin, processes for their preparation and their use in the treatment of vaginal infections |
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2017
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| CN101031572A (en) * | 2004-07-22 | 2007-09-05 | 坎布里制药公司 | (r/s) rifamycin derivatives, their preparation and pharmaceutical compositions |
| CN103732212A (en) * | 2011-07-29 | 2014-04-16 | 意大利阿尔法韦士曼制药公司 | Pharmaceutical compositions comprising rifaximin, processes for their preparation and their use in the treatment of vaginal infections |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109464673A (en) * | 2019-01-08 | 2019-03-15 | 丹诺医药(苏州）有限公司 | Application and the preparation of rifamycin-quinolizine ketone coupling molecule and its salt |
| WO2020143535A1 (en) * | 2019-01-08 | 2020-07-16 | 丹诺医药(苏州）有限公司 | Use and formulation of rifamycin-quinazinone coupling molecule |
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