CN108310393A - A kind of application of rifamycin-quinolizine ketone coupling molecule - Google Patents
A kind of application of rifamycin-quinolizine ketone coupling molecule Download PDFInfo
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- CN108310393A CN108310393A CN201810145498.9A CN201810145498A CN108310393A CN 108310393 A CN108310393 A CN 108310393A CN 201810145498 A CN201810145498 A CN 201810145498A CN 108310393 A CN108310393 A CN 108310393A
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- Prior art keywords
- mycobacterium
- rifamycin
- mycobacteria
- coupling molecule
- 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
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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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
Abstract
The present invention provides a kind of rifamycin quinolizine ketone coupling molecules, or its stereoisomer, hydrate, deuterated object, ester, solvate, crystal form, metabolite, pharmaceutically acceptable salt or prodrug, application in anti-non-tuberculous mycobacteria, the rifamycin quinolizine ketone coupling molecule have structure shown in formula I：
Description
Technical field
The present invention relates to a kind of applications of rifamycin-quinolizine ketone coupling molecule, belong to pharmaceutical technology field.
Background technology
Non-tuberculous mycobacteria (non-tuberculous mycobacteria, NTM) is also once known as atypia branch bar
Bacterium refers to removing mycobacterium tuberculosis complex (mycobacterium tuberculosis complex, MTC) and leprosy branch
Mycobacteria other than bacillus (Mycobacterium leprae).There are many mycobacteria sorting techniques, to clinical guidance
Meaning considers, NTM is simply divided into fast growth mycobacteria (rapidly growing mycobacteria, RGM) and slow life
Long mycobacteria (slowly growing mycobacteria, SGM), you can medication is selected to provide advantageous information.In view of solid
The popularization of body culture, this sorting technique can be implemented without special technique and operation bidirectional, therefore highly practical.RGM is solid
It is cultivated on body culture medium and obtains naked eyes visible colonies in 3-7 days, and SGM then needs several weeks.Clinic is most common clinical valence
The RGM of value includes mycobacterium abscessus (Mycobacterium abscessus), mycobacterium fortutitum (Mycobacterium
Fortuitum) and macrolides, amino are usually selected in Mycobacterium chelonei (Mycodacterium chelonei), RGM infection
The drug therapies such as glycoside and fluoroquinolones.It is most common that have the SGM of clinical value include the compound group of mycobacterium avium
(Mycobacterium avium complex, MAC include mainly mycobacterium avium (Mycobacterium avium) and born of the same parents
Mycobacterium intracellulare (Mycobacterium intracellulare)), mycobacterium kansasii (Mycobacterium
Kansasii) and mycobacterium xenopi (Mycobacterium xenopi) etc., treat and usually choose macrolides and Li Fu
Mycin class oral drugs sometimes add with injection class antituberculotic.
Currently, increasing trend is presented in the incidence of NTM infection, has become in many countries and threatens the important of human health
Public health problem.The all previous tuberculosis epidemiology survey data of China shows, NTM separation rates are by 4.3% in 1979
Rise to 11.1% in 2000, to 2010 21%, in the situation obviously risen.In the certain provinces of China, NTM bacterium mainly by
Mycobacterium avium, mycobacterium abscessus and Mycobacterium intracellulare cause.And in the U.S., then with mycobacterium avium, abscess branch bar
Based on bacterium and mycobacterium kansasii.Due to cause NTM infect mycobacterial species it is different, have the different speeds of growth and
Characteristic, and the tolerance different to antibacterials, therefore prolonged antibiotic therapy is generally required, success rate is low and adjoint
Significant side effect.Especially in recent years NTM has a growth trend to the drug resistance of existing drug, and the drug effect of existing drug is into one
Step reduces.It develops and global public health and great demand clinically is had become to the new medicine and method that NTM infects.
Invention content
In view of the problems of the above-mentioned prior art, the object of the present invention is to provide a kind of rifamycin-quinolizine ketone couplings
The application of molecule, the rifamycin-quinolizine ketone coupling molecule can effectively inhibit and kill the main pathogen for causing NTM to infect
Bacterium, and then for treating NTM infection.
The purpose of the present invention is achieved by the following technical programs：
A kind of rifamycin-quinolizine ketone coupling molecule or its stereoisomer, hydrate, deuterated object, ester, solvate,
Crystal form, metabolite, pharmaceutically acceptable salt or prodrug, the application in anti-NTM (i.e. non-tuberculous mycobacteria), the profit good fortune
Mycin-quinolizine ketone coupling molecule has structure shown in formula I：
In above-mentioned application, it is preferred that the NTM may include mycobacterium avium, mycobacterium abscessus, Kansas branch
Bacillus, Mycobacterium intracellulare, it is one or more in Marseille mycobacteria, Mycobacterium chelonei and mycobacterium fortutitum.
In above-mentioned application, it is preferred that the NTM can be mycobacterium avium, mycobacterium abscessus and Kansas branch
It is one or more in bacillus.
The present invention also provides above-mentioned rifamycin-quinolizine ketone coupling molecule or its stereoisomers, hydrate, deuterated
Object, ester, solvate, crystal form, metabolite, pharmaceutically acceptable salt or prodrug treat the non-tuberculosis branch of human body preparing
Application in the drug of disease caused by bacillus infection.
The present invention also provides a kind of drug combination composition of anti-non-tuberculous mycobacteria, on combination component may include
The rifamycin stated-quinolizine ketone coupling molecule or its stereoisomer, hydrate, deuterated object, ester, solvate, crystal form, generation
Thank product, pharmaceutically acceptable salt or prodrug.
Said medicine combination composition may include the antimicrobial of rifamycin-quinolizine ketone coupling molecule and this field routine
The combination of the antibacterials of the combination of object, the salt of rifamycin-quinolizine ketone coupling molecule and this field routine, rifamycin-quinoline
The mixture of piperazine ketone coupling molecule and its salt and combination, the rifamycin-quinolizine ketone coupling of the antibacterials of this field routine divide
Stereoisomer, hydrate, deuterated object, ester, solvate, crystal form, metabolite, pharmaceutically acceptable salt or the prodrug of son
At least one of combination with the antibacterials of this field routine.
The present invention also provides above-mentioned drug combination compositions to cause in preparation treatment human body non-tuberculous mycobacteria infection
Disease drug in application.
The present invention protrusion effect be：
Rifamycin-quinolizine ketone the coupling molecule or its stereoisomer, hydrate, deuterated object, ester, solvent of the present invention
Compound, crystal form, metabolite, pharmaceutically acceptable salt or prodrug can effectively antagonize NTM, and then for treating human body NTM
Infection.
Specific implementation mode
In order to which technical characteristic, purpose and the advantageous effect to the present invention are more clearly understood, now to the skill of the present invention
Art scheme carry out it is described further below, but should not be understood as to the present invention can practical range restriction.Institute in following embodiments
Experimental method is stated, is conventional method unless otherwise specified；The reagent and material unless otherwise specified can be from business ways
Diameter obtains.
Embodiment 1
The present embodiment provides a kind of rifamycin-application of the quinolizine ketone coupling molecule in anti-NTM, the rifamycin-quinolines
Piperazine ketone coupling molecule has structure shown in formula I：
In the present embodiment, using the rifamycin-quinolizine ketone coupling molecule (formula I) and positive control of the present invention to non-knot
Pathogen mycobacterium avium, mycobacterium abscessus and mycobacterium kansasii belonging to core mycobacteria etc. carry out antibacterial test.
Obtain minimum inhibitory concentration (Minimum Inhibitory Concentration, MIC) and minimum bactericidal concentration (Minimum
Bactericidal Concentration, MBC).Clarithromycin, Moxifloxacin, amikacin, rifampin, Rifabutin, ring
Third husky star and metronidazole are as positive control.Test strain is provided by KnowBio companies.Chinese Clinical isolated strains come from
Hospital of Hai Fei sections.
The antibacterial test of the present embodiment is tested using the micro broth dilution method of two kinds of different culture medias：(1) MH is micro-
Measure broth dilution method, using MH culture mediums (or culture solution), the calcium ions and magnesium ions recommended density of MH meat soups (cation adjust) with face
Bed and laboratory standard research institute (Clinical and Laboratory Standards Institute, CLSI；M7-A7)
Guide it is consistent.(2) the micro broth dilution methods of 7H9 use 7H9 culture mediums (or culture solution, Sigma-Aldrich are provided).Make
The reasons why carrying out composite sifting with two kinds of culture mediums of MH and 7H9 is the compound of anti-mycobacteria in different fluid nutrient mediums
Show different bacteriostatic activities, the embodiment of the present invention by micro broth dilution method using different broth bouillons come
Optimize and the NTM susceptibility carried out is detected, is closer to clinical condition.
The method of minimum inhibitory concentration test is as follows：
By the non-tuberculous mycobacteria of fast-growth (RGM) on the agar plate (Sigma-Aldrich offers) of 7H11
It is grown in 35-37 DEG C of air environment 3 days or so (depending on bacterium bacterial strain).Non-tuberculous point of (SGM) will slowly be grown
Branch bacillus grows 21-30 days on agar 7H11 plates (Sigma-Aldrich offers) in 37 DEG C of air environment.
The certain bacterium colony of picking from agar plate is placed in MH the or 7H9 culture solutions with 0.05% Tween-80,
And by the culture of 3 days (fast-growths) or 12 days (slowly growth) to absorbance (OD in the air environment at 35-37 DEG C
Value) it is 0.08-0.1 (0.5 Maxwell standard).Then it is 0.08-0.1 to be prepared into absorbance (OD600 values) by physiological saline
(0.5 Maxwell standard) bacterial suspension.
180 μ L meat soups (MH or 7H9 culture solutions) are added in first row in 96 orifice plates.Then by 100 μ L meat soups (MH or
It 7H9) is added in other holes in 96 orifice plates.Type I compound is made into 1.28mg/mL solution using DMSO, and is immediately used to 64-
The test of 0.062 μ g/mL ranges.The compound of 20 μ L is added in first row hole and takes 100 μ L serial dilutions.Finally, by 100
μ L non-tuberculous mycobacteria bacterial strain suspension is added in all holes in addition to culture medium control wells.The quality control of each microorganism
Reagent is different.This some holes includes：1) only germy negative control, 2) negative control for there was only culture medium, 3) clarithromycin etc.
Positive control, 4) optional Escherichia coli control.
RGM measures OD values on day 3, and SGM was measured at the 12nd day.The sword recommended using clinical and laboratory standard research institute
The method of reddish black (Resazurin) microtitration assay plate is measured.In short, this method is by resazurin (7- hydroxyls-
3H- benzene oxazines -3- ketone 10- oxides) it is added in 96 orifice plates.Resazurin is a kind of blue dyes, hypofluorescence itself can not
Reversibly it is reduced into the fluorescent dye of pink and height red.It is used as the redox instruction during live bacteria MIC is measured
Agent.
The assay method of minimum bactericidal concentration is as follows：
It is higher than the holes MIC concentration (dilution 0-1-2-3-4-5-6-7) by the culture solution and concentration by concentration in MIC
Culture solution carries out coated plate on 7H11 or MH agar plates, and quadruplicate (four plate/holes) (is depended on to determine at 35-37 DEG C
In bacterium bacterial strain) and air environment in cultivate and calculate CFU.MIC90 is the lowest concentration of drug for inhibiting 90%NTM separation strains.
MBC99 is the lowest concentration of drug for the starting bacteria for killing 99.99%.
Test result is as follows shown in table 1-3：
1 rifamycin of table-quinolizine ketone coupling molecule (formula I) to the minimum inhibitory concentration of non-tuberculous mycobacteria (MIC, it is micro-
Grams per milliliter)
2 rifamycins of table-quinolizine ketone coupling molecule (formula I) to the minimum bactericidal concentration of non-tuberculous mycobacteria (MBC, it is micro-
Grams per milliliter)
3 rifamycins of table-quinolizine ketone coupling molecule (formula I) to the minimum inhibitory concentration of Chinese Clinical isolation (MIC,
Mcg/ml, MH culture mediums)
By upper table 1, table 2 and table 3 as it can be seen that rifamycin-quinolizine ketone coupling molecule (formula I) of the present invention is to mycobacterium avium
The minimum inhibitory concentration (MIC) of smooth type and rough type is similar with amikacin, is better than clarithromycin.Compound I is to Kansas
The activity of mycobacteria is much higher than rifampin, Ciprofloxacin and metronidazole, similar to other control compounds.It is to intracellular point
The activity of branch bacillus is weak.On minimum bactericidal concentration (MBC), rifamycin-quinolizine ketone coupling molecule (formula I) is to Kansas branch
It is better than or is much stronger than other antibiotic medicines of all detections on the bactericidal activity of bacillus.To mycobacterium avium smooth type bacterial strain
Also active.Meanwhile the measurement result on two different culture mediums is almost the same, can be adapted to clinical application.Result of study
Show that rifamycin-quinolizine ketone coupling molecule (formula I) of the present invention has the external activity of effective and a wider spectrum anti-NTM, it can
For treatment human body NTM infection.
In addition, stereoisomer, hydrate, the deuterium of rifamycin-quinolizine ketone coupling molecule described in the embodiment of the present invention
It can be used for resisting non-tuberculosis branch bar for object, ester, solvate, crystal form, metabolite, pharmaceutically acceptable salt or prodrug
Bacterium is used to prepare the drug of disease caused by treatment human body non-tuberculous mycobacteria infection.
In another embodiment, the above-mentioned rifamycin of the embodiment of the present invention-quinolizine ketone coupling molecule
Stereoisomer, hydrate, deuterated object, ester, solvate, crystal form, metabolite, pharmaceutically acceptable salt or prodrug also may be used
To form combination composition with the conventional antimicrobial drug of this field, for treating the caused disease of NTM infection.
Claims (6)
1. a kind of rifamycin-quinolizine ketone coupling molecule or its stereoisomer, hydrate, deuterated object, ester, solvate, crystalline substance
Type, metabolite, pharmaceutically acceptable salt or prodrug, the application in anti-non-tuberculous mycobacteria, the rifamycin-quinolizine
Ketone coupling molecule has structure shown in formula I：
2. application according to claim 1, it is characterised in that：The non-tuberculous mycobacteria includes mycobacterium avium, purulence
Swollen mycobacteria, mycobacterium kansasii, Mycobacterium intracellulare, Marseille mycobacteria, Mycobacterium chelonei and mycobacterium fortutitum
In it is one or more.
3. application according to claim 2, it is characterised in that：The non-tuberculous mycobacteria is mycobacterium avium, abscess
It is one or more in mycobacteria and mycobacterium kansasii.
4. rifamycin described in claim 1-quinolizine ketone coupling molecule or its stereoisomer, hydrate, deuterated object, ester,
Solvate, crystal form, metabolite, pharmaceutically acceptable salt or prodrug treat human body non-tuberculous mycobacteria sense preparing
Application in the drug of disease caused by dye.
5. a kind of drug combination composition of anti-non-tuberculous mycobacteria, combination component includes sharp good fortune described in claim 1
Mycin-quinolizine ketone coupling molecule or its stereoisomer, hydrate, deuterated object, ester, solvate, crystal form, metabolite, medicine
Acceptable salt or prodrug on.
6. the disease caused by preparing treatment human body non-tuberculous mycobacteria infection of the drug combination composition described in claim 5
Drug in application.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810145498.9A CN108310393A (en) | 2018-02-12 | 2018-02-12 | A kind of application of rifamycin-quinolizine ketone coupling molecule |
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| CN201810145498.9A CN108310393A (en) | 2018-02-12 | 2018-02-12 | A kind of application of rifamycin-quinolizine ketone coupling molecule |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
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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 |
| US20140371228A1 (en) * | 2011-12-22 | 2014-12-18 | The Trustees Of The University Of Pennsylvania | Novel therapeutic agents |
| CN106535877A (en) * | 2014-05-15 | 2017-03-22 | 英斯梅德股份有限公司 | Methods for treating pulmonary non-tuberculous mycobacterial infections |
-
2018
- 2018-02-12 CN CN201810145498.9A patent/CN108310393A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101031572A (en) * | 2004-07-22 | 2007-09-05 | 坎布里制药公司 | (r/s) rifamycin derivatives, their preparation and pharmaceutical compositions |
| US20140371228A1 (en) * | 2011-12-22 | 2014-12-18 | The Trustees Of The University Of Pennsylvania | Novel therapeutic agents |
| CN106535877A (en) * | 2014-05-15 | 2017-03-22 | 英斯梅德股份有限公司 | Methods for treating pulmonary non-tuberculous mycobacterial infections |
Non-Patent Citations (1)
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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