CN106822119A - A kind of new application of rifamycin nitroimidazole coupling molecule - Google Patents
A kind of new application of rifamycin nitroimidazole coupling molecule Download PDFInfo
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- CN106822119A CN106822119A CN201710109977.0A CN201710109977A CN106822119A CN 106822119 A CN106822119 A CN 106822119A CN 201710109977 A CN201710109977 A CN 201710109977A CN 106822119 A CN106822119 A CN 106822119A
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- rifamycin
- anaerobism
- intestines
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- 0 CC(CC1=C2CC(*=C)C(C(C)=CC=C[C@](C)[C@@]([C@@](C)[C@@](*)[C@@](C)[C@@]([C@](C)CC=CO[C@](C)(C3=O)O4)OC(C)=O)O)=O)C5(CC*(CCC6=C7C(C)=CCC=C(C)C67)CC5)*=C1c1c3c4c(C)c(OC)c1C2=O Chemical compound CC(CC1=C2CC(*=C)C(C(C)=CC=C[C@](C)[C@@]([C@@](C)[C@@](*)[C@@](C)[C@@]([C@](C)CC=CO[C@](C)(C3=O)O4)OC(C)=O)O)=O)C5(CC*(CCC6=C7C(C)=CCC=C(C)C67)CC5)*=C1c1c3c4c(C)c(OC)c1C2=O 0.000 description 1
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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
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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Abstract
Present invention is disclosed application of the rifamycin nitroimidazole coupling molecule shown in a kind of formula I in intestines and stomach anaerobism or amphimicrobian ammonia-producing bacterium group is suppressed.The rifamycin nitroimidazole coupling molecule of formula I is similar with the antimicrobial spectrum of rifaximin, there is stronger antibacterial activity to the common anaerobism of intestines and stomach or amphimicrobian ammonia-producing bacterium group, there is the characteristic for producing spontaneous Resistant frequency low simultaneously, there is good application prospect in terms of the prevention in hepatic encephalopathy or to related anaerobic infection and treatment.
Description
Technical field
The invention belongs to medicinal chemistry arts, more particularly to a kind of rifamycin-nitroimidazole coupling molecule new application.
Background technology
Hepatic encephalopathy (Hepatic Encephalopathy, HE) be acute and chronic End-stage liver disease and cirrhosis it is important simultaneously
One of hair disease, has a strong impact on prognosis and the quality of life of patient.Once there is HE in patients with chronic liver, survival rate is no more than within 1 year
50%, survival rate is no more than 25% within 3 years.Invisible hepatic encephalopathy therein (Covert Hepatic Encephalopathy,
CHE) patient clinical could find usually without notable symptom only by neuropsychological test.According to statistics, at least 30% cirrhosis
Patient can occur together different degrees of HE.The Chinese recent investigation discovery to 13 provinces and cities, 16 Grade A hospitals, CHE in inpatient
Incidence be up to 39.9%.CHE patient is often usually ignored, the Working Life as normal person.But more and more grind
Study carefully and show that CHE is the main cause for causing liver cirrhosis patient cognition dysfunction, the quality of life and worksheet of patient can be influenceed
It is existing, increase motor vehicle accident risk, and increase to dominant hepatic encephalopathy (Overt Hepatic Encephalopathy, OHE)
The risk of development.Ammonia poisoning is the main mechanism that HE/CHE occurs, and liver cirrhosis patient intestinal flora hyper-proliferative, intestinal wall are hypertonic
Saturating state, Instestinal motility disorder cause intestinal bacterium displacement, endotoxemia high and hyperammonemia jointly, so as to induce HE/
CHE, aggravates liver damage, forms vicious circle.
The pathogenesis of hepatic encephalopathy (including slight type hepatic encephalopathy) is more complicated, and ammonia poisoning theory is considered as liver property
The main pathogenesis of encephalopathic, therefore suppress ammonia-producing bacterium growth, the absorption for reducing ammonia and the discharge for strengthening ammonia are drug therapies
Main Means.Currently used for fiest-tire medication (Hepatology, 2014,60,715 of HE/CHE；Journal of
Hepatology, 2014,61,642.) lactulose and rifaximin are mainly, it is micro- by suppressing enteric bacteria or improvement enteron aisle
Ecologic structure, reduction enteron aisle ammonia absorb and play a role.But, lactulose has abdominal distension, diarrhoea etc. as oral non-absorbent disaccharide
Adverse reaction, many patients are difficult to tolerate；And rifaximin is expensive, and there is the risk produced to its resistance.Therefore, open
Hair has antimicrobial spectrum wide to ammonia-producing bacterium, and antibacterial activity has great meaning better than the new HE/CHE medicines of rifaximin
Justice.
Disclosed in United States Patent (USP) US 7,678,791B2 compound 4- deoxidations -3,4- [2- volutions-[2- (2- methyl -
5- nitro-imidazol -1- bases) ethyl]-piperidin-4-yl]]-(1 hydrogen)-imidazo-(2,5- dihydro) rifamycin-S, the compound
There is antimicrobial acivity to several bacteriums such as gram-positive bacteria and Escherichia coli, but be not documented it to intestines and stomach
Ammonia-producing bacterium group has antibacterial 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 rifamycin-nitroimidazole idol
Join the new application of molecule, can effectively suppress intestines and stomach anaerobism or amphimicrobian ammonia-producing bacterium group, can be used in treating hepatic encephalopathy.
The purpose of the present invention will be achieved by the following technical programs：
Rifamycin-nitroimidazole coupling molecule shown in a kind of formula I is suppressing intestines and stomach anaerobism or amphimicrobian product ammonia
Application in flora (urease-positive)；
Preferably, in above-mentioned application, wherein, the intestines and stomach anaerobism or amphimicrobian ammonia-producing bacterium group include baby's bifid
Bacillus subspecies (Bifidobacterium infantis subsp.Infantis), bacteroides fragilis (Bacteroides
Bifidum), clostridium perfringens (Clostridium perfringens), slow Ai Gete bacterium
(Eggerthella lenta), fusobacterium necrophorum (Fusobacterium necrophorum), Eubacterium rectale
(Eubacterium rectale), clostridium difficile (Clostridium difficile), helicobacter pylori (Helicobacter
Pylori), Lactobacillus salivarius (Lactobacillus salivarius) and peptostreptococcus prevotii
One or more in (Peptostreptococcus prevoti) of combination..
The present invention also provides above-mentioned rifamycin-nitroimidazole coupling molecule and is treated by intestines and stomach anaerobism as preparation
Or in the medicine of hepatic encephalopathy (Hepatic Encephalopathy, HE) that causes of amphimicrobian ammonia-producing bacterium group's imbalance should
With.
The present invention also provides above-mentioned rifamycin-nitroimidazole coupling molecule and is treated by intestines and stomach anaerobism as preparation
Or the invisible hepatic encephalopathy (Covert Hepatic Encephalopathy, CHE) that the group's imbalance of amphimicrobian ammonia-producing bacterium causes
Medicine in application.
Preferably, in above-mentioned application, the human body effective dose of the rifamycin-nitroimidazole coupling molecule is 10-
10000mg, treatment cycle is at least 2 days.
Preferably, in above-mentioned application, it is drug administration by injection, oral administration, chamber that the administering mode that the application is used includes
The combination of one or more in interior 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：The rifamycin of formula I-nitroimidazole coupling molecule is anti-with rifaximin
Bacterium spectrum is similar, but has stronger antibacterial activity to intestines and stomach anaerobism or amphimicrobian ammonia-producing bacterium group, while having Resistant frequency
Low characteristic, has good application prospect in terms of the prevention and treatment of hepatic encephalopathy.
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
Rifamycin-nitroimidazole coupling molecule that the present embodiment provides shown in formula I is suppressing intestines and stomach anaerobism or facultative
Application in anaerobism ammonia-producing bacterium；
Wherein, the intestines and stomach anaerobism or amphimicrobian ammonia-producing bacterium group include bifidobacterium infantis subspecies, bacteroides fragilis,
Clostridium perfringens, slow Ai Gete bacterium, fusobacterium necrophorum, Eubacterium rectale, clostridium difficile, helicobacter pylorus
Bacterium, one or more in Lactobacillus salivarius and peptostreptococcus prevotii of combination.
In the present embodiment, chemical compounds I rifamycin-nitroimidazole coupling molecule is cooked by the pathogen related to hepatic encephalopathy
Susceptibility test experience, pathogen includes above-mentioned anaerobism ammonia-producing bacterium group.Test is used and clinical and laboratory standard research institute
(Clinical and Laboratory Standards Institute,CLSI；The consistent agar dilution of guide 1-3),
Carry out under anaerobic.Control group compound is metronidazole, and sharp Fu puts down, rifaximin and Ciprofloxacin.
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, the microbionation that will be freezed is to suitable agar ware in Bactron
35 degrees Celsius grow 48 hours in II anaerobics cabinet (Shel Lab, Cornelius, OR).
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 is determined using the agar dilution (1-2) in CLSI.According to CLSI guides (1-2) hand
Work carries out drug dilution and prepares the agar plate of drug containing.To dry agar surface, porous plate is placed 1 hour in room temperature.
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 turbid to 0.5 Mai Kefalanshi in suitable culture medium
Scale is accurate.Then each bacterial suspension is transferred in the hole of detection plate with stainless steel reproducer.Greatly containing about 105/ 1-2 microlitres
To the agar surface per hole, anaerobic environment 35 is Celsius in being put into anaerobic cabinet by medicine plate and without medicine control board after drying for microbionation
Degree nurture 42-48 hours.Determine MIC (1-2) according to CLSI guides after culture.
Test result such as table 1 shows.
Table 1
From above-mentioned test result, chemical compounds I is to including bifidobacterium infantis subspecies, bacteroides fragilis, perfringens
Clostruidium, slow Ai Gete bacterium, fusobacterium necrophorum, Eubacterium rectale, clostridium difficile, helicobacter pylori, saliva breast
Bacillus and peptostreptococcus prevotii have than rifaximin (10-100 in interior most of intestines and stomach anaerobism or facultative ammonia-producing bacterium
Times) or the stronger bacteriostatic activity of metronidazole (more than 1000 times).
Thus the effective dose of compound I is speculated as the 1/100 of rifaximin, equivalent to daily 10 milligrams.To reach more
Good drug effect, the dosage of compound I can continue to increase to 10000 milligrams to reach its highest effective dose.
Embodiment 2
The present embodiment provides a kind of quick release oral formulations of the rifamycin-nitroimidazole coupling molecule shown in formula I
Prescription and preparation method.
Rifamycin-nitroimidazole coupling 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 rifamycin-nitroimidazole coupling molecule, mannitol and carboxyrnethyl starch sodium (DST) cross 30 mesh sieves, in addition granulator,
Premix, impeller mixing speed 700rpm, about 15 minutes time.Added within (145-165g/ minutes) with fixed speed with peristaltic pump again
Appropriate purified water and binder in granulator mixture, granulator impeller mixing speed 400rpm, about 1~2 minute time,
Binder is added after finishing, and continues 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 will
Silica is put in hopper blender with dry particl and is mixed, incorporation time 15 minutes；Rotating speed 20rpm；Add stearic acid
Magnesium, incorporation time 6 minutes, mixing velocity is 20rpm, takes the material survey after total mixing and fills No. 0 capsule using capsule filling machine, i.e.,
Obtain the rifamycin-nitroimidazole coupling molecule hard capsule shown in formula I.
Material after total mixing is used into tabletting machine, the rifamycin-nitroimidazole coupling 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-nitroimidazole coupling 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-nitroimidazole coupling molecule, moderate-speed mixer 10-15 minutes, the rifamycin-nitro miaow shown in moistening type I
Azoles coupling molecule, 1N NaOH are slowly added dropwise, time-consuming about 175 minutes (preceding fast rear slow), the rifamycin-nitro miaow shown in formula I
Azoles coupling 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-nitroimidazole coupling point shown in formula I is obtained final product after Zha Gai
The freeze drying powder injection of son.
Embodiment 4
It is prepared by a kind of enteric controlled-release preparation that the present embodiment provides the rifamycin-nitroimidazole coupling molecule shown in formula I
Method.
Medicine-containing particle prescription
Protective layer prescription：
Mannitol 50g
Sucrose 8g
Hydroxypropyl methylcellulose 3.2g
Enteric coat layer
Hydroxypropyl methylcellulose phthalate (HPMCP) 32g
Talcum powder 1.86g
Take rifamycin-nitroimidazole coupling molecule 2g, mannitol 20g, the hydroxymethyl starch shown in starch 80g, formula I
(CMS) 4g, lauryl sodium sulfate 2g dry-mixings, prepare 4% hydroxypropyl methylcellulose phthalate (CMS) solution with
95% ethanol mixes (2 in proportion：8) it is binder, prepares medicine-containing particle；
50g mannitol is dissolved in remaining CMS solution, medicine-containing particle surface is wrapped in, then by recipe quantity syrup with
95% ethanol mixes (44 by a certain percentage：56), sprinkling and particle surface, as protective layer.
The 7.5%HPMCP of recipe quantity is finally mixed (80 by a certain percentage with 95% ethanol：20), as enteric coating
Layer is wrapped in particle surface.
Compressing tablet is carried out after particle drying, whole grain, the small intestine of the rifamycin-nitroimidazole coupling molecule shown in formula I is obtained final product
Positioning postpones drug release tablet
It can be seen that, rifamycin-nitroimidazole coupling molecule (formula I) of the invention is to the common anaerobism of intestines and stomach or facultative detests
Oxygen ammonia-producing bacterium group has the antibacterial activity more stronger than rifaximin, while there is the low characteristic of Resistant frequency, for hepatic encephalopathy
And/or invisible hepatic encephalopathy will be with obvious therapeutic action.Simultaneously will be to by belonging to other senses that anaerobic species cause together
It is infected with therapeutic action.
Claims (7)
1. the rifamycin shown in a kind of formula I-nitroimidazole coupling molecule is suppressing intestines and stomach anaerobism or amphimicrobian ammonia-producing bacterium
Application in group；
2. application according to claim 1, it is characterised in that the intestines and stomach anaerobism or amphimicrobian ammonia-producing bacterium group include
It is bifidobacterium infantis subspecies, bacteroides fragilis, clostridium perfringens, slow Ai Gete bacterium, fusobacterium necrophorum, straight
Intestines Eubacterium, clostridium difficile, helicobacter pylori, one or more in Lactobacillus salivarius and peptostreptococcus prevotii of combination.
3. the rifamycin described in claim 1-nitroimidazole coupling molecule is treated by intestines and stomach anaerobism or simultaneous as preparation
Property the medicine of hepatic encephalopathy that causes of anaerobism ammonia-producing bacterium group's imbalance in application.
4. the rifamycin described in claim 1-nitroimidazole coupling molecule is treated by intestines and stomach anaerobism or simultaneous as preparation
Property the medicine of invisible hepatic encephalopathy that causes of anaerobism ammonia-producing bacterium group's imbalance in application.
5. the application according to claim 3 or 4, it is characterised in that the people of the rifamycin-nitroimidazole coupling molecule
Body effective dose is 10-10000mg, and treatment cycle is at least 2 days.
6. the application according to claim 3 or 4, it is characterised in that the administering mode that the application is used includes being administered to
The combination of one or more in medicine, oral administration, intracavitary administration, enteral administration and Transdermal absorption.
7. the application according to claim 3 or 4, it is characterised in that the form of administration that the application is used includes injection
The combination of one or more in agent, suppository, tablet, capsule, patch and sustained release agent.
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| CN201710109977.0A CN106822119A (en) | 2017-02-28 | 2017-02-28 | A kind of new application of rifamycin nitroimidazole coupling molecule |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047250A (en) * | 2018-02-12 | 2018-05-18 | 丹诺医药(苏州）有限公司 | A kind of application of rifamycin-nitroimidazole coupling molecule |
| EP3421616A1 (en) * | 2017-06-29 | 2019-01-02 | Tata Consultancy Services Limited | Method and system for monitoring the gut health of an individual |
| CN109453166A (en) * | 2018-10-16 | 2019-03-12 | 丹诺医药(苏州）有限公司 | A kind of solid dispersions of rifamycin-quinolizine ketone coupling molecule and its application |
| CN109453165A (en) * | 2018-10-16 | 2019-03-12 | 丹诺医药(苏州）有限公司 | A kind of solid dispersions of rifamycin-nitroimidazole coupling molecule and its application |
| WO2024036578A1 (en) * | 2022-08-18 | 2024-02-22 | Tennor Therapeutics (Suzhou) Limited | Methods for preventing or treating h. pylori infection |
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| WO2008008480A2 (en) * | 2006-07-12 | 2008-01-17 | Cumbre Pharmaceuticals Inc. | Nitroheteroaryl-containing rifamycin derivatives |
| CN102245615A (en) * | 2008-10-02 | 2011-11-16 | 萨利克斯药品有限公司 | Methods of treating hepatic encephalopathy |
| CN104971061A (en) * | 2015-06-09 | 2015-10-14 | 丹诺医药(苏州）有限公司 | Novel application of rifamycin-nitroimidazole coupling molecule |
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2017
- 2017-02-28 CN CN201710109977.0A patent/CN106822119A/en active Pending
Patent Citations (3)
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|---|---|---|---|---|
| WO2008008480A2 (en) * | 2006-07-12 | 2008-01-17 | Cumbre Pharmaceuticals Inc. | Nitroheteroaryl-containing rifamycin derivatives |
| CN102245615A (en) * | 2008-10-02 | 2011-11-16 | 萨利克斯药品有限公司 | Methods of treating hepatic encephalopathy |
| CN104971061A (en) * | 2015-06-09 | 2015-10-14 | 丹诺医药(苏州）有限公司 | Novel application of rifamycin-nitroimidazole coupling molecule |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3421616A1 (en) * | 2017-06-29 | 2019-01-02 | Tata Consultancy Services Limited | Method and system for monitoring the gut health of an individual |
| CN108047250A (en) * | 2018-02-12 | 2018-05-18 | 丹诺医药(苏州）有限公司 | A kind of application of rifamycin-nitroimidazole coupling molecule |
| CN108047250B (en) * | 2018-02-12 | 2020-08-14 | 丹诺医药(苏州）有限公司 | Application of rifamycin-nitroimidazole coupled molecule |
| CN109453166A (en) * | 2018-10-16 | 2019-03-12 | 丹诺医药(苏州）有限公司 | A kind of solid dispersions of rifamycin-quinolizine ketone coupling molecule and its application |
| CN109453165A (en) * | 2018-10-16 | 2019-03-12 | 丹诺医药(苏州）有限公司 | A kind of solid dispersions of rifamycin-nitroimidazole coupling molecule and its application |
| WO2024036578A1 (en) * | 2022-08-18 | 2024-02-22 | Tennor Therapeutics (Suzhou) Limited | Methods for preventing or treating h. pylori infection |
| US12005050B2 (en) | 2022-08-18 | 2024-06-11 | Tennor Therapeutics (Suzhou) Limited | Methods for preventing or treating H. pylori infection |
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