CN109481445A - Composition containing morpholine ketone compounds - Google Patents
Composition containing morpholine ketone compounds Download PDFInfo
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- CN109481445A CN109481445A CN201811562463.1A CN201811562463A CN109481445A CN 109481445 A CN109481445 A CN 109481445A CN 201811562463 A CN201811562463 A CN 201811562463A CN 109481445 A CN109481445 A CN 109481445A
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of composition containing the combined system being made of first morpholine ketone compounds of the different and molar ratio in 0.01~100 range and the second morpholine ketone compounds, the mixed system can generate the bacteriostasis of collaboration.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of composition containing morpholine ketone compounds.
Background technique
Infectious diseases is the major class disease caused by the microorganism infections such as bacterium, helminth, fungi or virus, can be passed through
Various approach are directly or indirectly propagated between human body.It is posted including antibiotic, antiviral agent, antifungal with anti-although having at present
A variety of anti-infectives such as infested medicine can be used for the treatment of infectious diseases, cause a disease in this disease still global range or lethal
One of the main reason for.2010, there are about 15,000,000 to die of infectious diseases in the whole world.
Although the antibiotic such as penicillins, cephalosporins, quinolones and synthetic antibacterial drug are applied in the mankind and thin
Huge effect has been played in the struggle of bacterium sexuality dye, has effectively contained the propagation of bacterial infection.But with above-mentioned antibacterial
The continuous of the application of medicine is popularized, and the bacterial drug resistance problem caused because of Irrational Use of Drugs becomes increasingly conspicuous.Therefore still having needs
Developing has the active drug of high-efficiency antimicrobial for partial resistance bacterium.
Morpholone is parent nucleus common in a variety of compound structures with antibacterial activity, such as JAOCS, 1998 (66)
6 result of study shows that fatty 2- morpholine ketone compounds have good suppression to bacteriums such as staphylococcus aureuses
Bacterium activity, however the test result of the present inventor is found, morpholine ketone compounds disclosed in the document are resistance to methicillin
The bacteriostatic activity of the drug tolerant bacterias such as pharmacological property staphylococcus aureus and vancomycin-resistant enterococcus is not fully up to expectations (not to be reached
50%).
It is well known that Chinese medicine can pass through a series of synergistic effect of the compound group (effective component) of similar structures
Its curative effect is embodied, therefore, in chemical antimicrobial field, there is the drug of similar structure by finding, by means of acting synergistically,
It is one of the approach for improving antimicrobial function and effect.
Summary of the invention
The purpose of the present invention is to provide a kind of composition containing morpholine ketone compounds, the composition has efficient
Bacteriostatic activity.
To achieve the goals above, one aspect of the present invention provides a kind of contain by different and molar ratio in 1:100
The composition for the combined system that the first morpholine ketone compounds and the second morpholine ketone compounds within the scope of~100:1 are constituted,
It is characterized in that, the first morpholine ketone compounds and the second morpholine ketone compounds are in following compound respectively
It is a kind of:
First morpholine ketone compounds of the present invention and the second morpholine ketone compounds are to be seen in the prior art
The compound of record, specifically, 1~compound of compound as described above 4 is seen in the record of CN106432218A, chemical combination
5~compound of object 10 is seen in " Chinese Journal of Pharmaceuticals ", and in the record of 2014,45 (4), compound 11 is seen in
In the record of WO2004060887.
According to the strong and weak sequence to act synergistically in bacteriostatic test, the preferably following combined system of combined system of the present invention
One of:
The combined system being made of compound 5 of the molar ratio in 0.5~1 range and compound 8,
The combined system being made of compound 1 of the molar ratio in 25~75 ranges and compound 5,
The combined system being made of compound 5 of the molar ratio in 0.25~0.75 range and compound 8,
The combined system being made of compound 5 of the molar ratio in 0.75~25 range and compound 8,
The combined system being made of compound 3 of the molar ratio in 0.01~0.25 range and compound 9,
The combined system being made of compound 1 of the molar ratio in 50~100 ranges and compound 5,
The combined system being made of compound 1 of the molar ratio in 25~75 ranges and compound 4,
The combined system being made of compound 2 of the molar ratio in 0.25~0.75 range and compound 10,
The combined system being made of compound 2 of the molar ratio in 0.01~0.25 range and compound 6,
The combined system being made of compound 3 of the molar ratio in 75~100 ranges and compound 5,
The combined system being made of compound 4 of the molar ratio in 50~100 ranges and compound 11,
The combined system being made of compound 2 of the molar ratio in 0.5~1 range and compound 4,
The combined system being made of compound 3 of the molar ratio in 0.01~0.5 range and compound 9,
The combined system being made of compound 7 of the molar ratio in 0.25~0.75 range and compound 11,
The combined system being made of compound 3 of the molar ratio in 50~100 ranges and compound 5,
The combined system being made of compound 8 of the molar ratio in 25~75 ranges and compound 10,
The combined system being made of compound 3 of the molar ratio in 0.01~50 range and compound 8,
The combined system being made of compound 2 of the molar ratio in 0.25~0.75 range and compound 4.
It is furthermore preferred that combined system of the present invention is selected from one of following combined system.
The combined system being made of compound 5 of the molar ratio in 0.5~1 range and compound 8,
The combined system being made of compound 1 of the molar ratio in 25~75 ranges and compound 5,
The combined system being made of compound 5 of the molar ratio in 0.25~0.75 range and compound 8,
The combined system being made of compound 5 of the molar ratio in 0.75~25 range and compound 8,
The combined system being made of compound 3 of the molar ratio in 0.01~0.25 range and compound 9,
The combined system being made of compound 1 of the molar ratio in 50~100 ranges and compound 5,
The combined system being made of compound 1 of the molar ratio in 25~75 ranges and compound 4,
The combined system being made of compound 2 of the molar ratio in 0.25~0.75 range and compound 10,
The combined system being made of compound 2 of the molar ratio in 0.01~0.25 range and compound 6.
Most preferably, combined system of the present invention is selected from one of following combined system:
The combined system that the compound 5 and compound 8 for being 0.75 by molar ratio are constituted,
The combined system that the compound 1 and compound 5 for being 50 by molar ratio are constituted,
The combined system that the compound 5 and compound 8 for being 0.5 by molar ratio are constituted,
The combined system that the compound 5 and compound 8 for being 1 by molar ratio are constituted,
The combined system that the compound 3 and compound 9 for being 0.01 by molar ratio are constituted,
The combined system that the compound 1 and compound 5 for being 75 by molar ratio are constituted,
The combined system that the compound 1 and compound 4 for being 50 by molar ratio are constituted,
The combined system that the compound 2 and compound 10 for being 0.5 by molar ratio are constituted,
The combined system that the compound 2 and compound 6 for being 0.01 by molar ratio are constituted,
Another aspect of the present invention provides the oral drug preparation containing composition as previously described, which is characterized in that described
The dosage form of preparation be one of selected from tablet, capsule and granule.
Preferably, the oral solid formulation further contains diluent and lubricant.Wherein, dilution of the present invention
Agent is more preferably pregelatinized starch, starch, dextrin, sucrose, microcrystalline cellulose, sorbierite, mannitol, lactose, calcium sulfate, phosphoric acid
One of hydrogen calcium and calcium phosphate；Lubricant of the present invention be more preferably sodium stearyl fumarate, stearic acid, magnesium stearate,
Calcium stearate, paraffin oil, paraffin, glycerin monostearate, monopalmitin, sodium acetate, sodium chloride, DL-leucine, the moon
One in lauryl sulfate, magnesium laurylsulfate, polyethylene glycol, polyoxyl 40 stearate and Brij30
Kind.
Oral solid formulation of the present invention can be used method well known to those of ordinary skill in the art and be prepared,
The method that specific method can refer to but be not limited in " pharmacy " (the 8th edition) that Fang Liang is edited, People's Health Publisher publishes.This
The preparation method of the invention granule be by combined system, diluent, mix lubricant to get.
The preparation method of capsule of the present invention is the filling glue by after combined system, diluent, mix lubricant
Capsule to get.
The preparation method of tablet of the present invention is to carry out tabletting for after combined system, diluent, mix lubricant,
To obtain the final product.
The content of combined system in oral solid formulation of the present invention and the dosage being thus related to can lead to
It crosses pharmacological testing well known to those of ordinary skill in the art to be screened and optimized, the present invention is to this without specifically limited.
Supplementary product consumption in oral solid formulation of the present invention can be by well known to those of ordinary skill in the art
Formulation method is screened and is optimized, and the present invention is to this without specifically limited.
Another aspect of the present invention provides the composition containing combined system as previously described in preparation for treating bacterium sense
Purposes in the drug of infectious diseases.
Preferably, bacterial infection disease of the present invention is by selected from Escherichia coli, pseudomonas aeruginosa, methoxy west
Woods Sensitive S. aureus, methicillin-resistant S staphylococcus, streptococcus pneumonia, vancomycin sensitive
One of enterococcus, vancomycin-resistant enterococcus, Acinetobacter bauamnnii, proteus mirabilis and Klebsiella Pneumoniae are thin
Disease caused by bacterium infection.
Extracorporeal bacteria inhibitor test is the results show that of the present invention contain the first morpholine ketone compounds and the second morpholine ketone
The combination of compound can produce bacteriostasis (the drug combination index for being added to collaboration in 0.01~100 molar ratio range
CI≤1)。
Specific embodiment
Below with reference to the embodiment of the present invention, clear, complete description is carried out to technical solution of the present invention, it is clear that retouched
The embodiment stated is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair
The range of bright protection.
Evaluation of the 1 morpholine ketone compounds of test example to the In Vitro Bacteriostasis of tested bacterium
Morpholine ketone compounds of the present invention (compound 1~16) are measured respectively using filter paper enzyme to each tested bacterium
In Vitro Bacteriostasis.Specifically, drawing prepared bacterial suspension (1 × 10 with liquid-transfering gun5/ mL, preparation method: will
It is activated on TSB culture medium [37 ± 1 DEG C, 3 days] for examination strain, oese is recycled to beat easily a small amount of bacterium from culture medium
Tongue fur is respectively added in the conical flask for being contained with 50mL sterile saline), uniformly it is applied to agar plate table after cooling
Plate containing bacterium is made in face.Sterilizing filter paper piece is taken, lets off in the tested material methanol solution of 2 times of incremental 6 kind concentration gradients and soaks respectively
1h is steeped, the 6mm circular filter paper piece impregnated is attached on the above-mentioned plate containing bacterium made, each culture dish (diameter 90mm) is sticked
The filter paper (filter paper is spaced identical as far as possible) of 3 dipped same molar concentration tested material methanol solutions, it is molten with 50% methanol
Liquid is as blank control.Processed plate containing bacterium is placed in 37 DEG C of insulating boxs and is cultivated for 24 hours, bacterium is measured using crossing method
Diameter is fallen, and calculates inhibiting rate (IR) according to following formula.
It is mapped using logarithm (log (c)) of the inhibiting rate (IR) to drug concentration (μM), and is linearly returned with Excel
Return, the first morpholine ketone compounds and the second morpholine ketone when generating specific depression effect (fa) are extrapolated according to regression equation
Close the concentration of object, i.e. ICfa(A)With ICfa(B)。
The combined system that test example 2 is made of the first morpholine ketone compounds and the second morpholine ketone compounds is to tested bacterium
In Vitro Bacteriostasis evaluation
The present invention is directed to the combined system counterpoise of each the first morpholine ketone compounds and the second morpholine ketone compounds
Test described in multiple parallel progress test example 1.
The first morpholine ketone compounds and the second morpholine ketone compounds are taken, after the mixing of specific molar ratio, with methanol
The solution of 6 concentration gradients is configured to for solvent.
Prepared bacterial suspension (1 × 10 is drawn with liquid-transfering gun5/ mL, preparation method: will be for examination strain in TSB
It is activated on culture medium [37 ± 1 DEG C, 3 days], recycles oese to beat easily a small amount of lawn from culture medium, be respectively added to contain
It is placed in the conical flask of 50mL sterile saline), it is uniformly applied to agar plate surface after cooling, plate containing bacterium is made.
Sterilizing filter paper piece is taken, is let off in the tested material methanol solution of 2 times of incremental 6 kind concentration gradients respectively and impregnates 1h, by what is impregnated
6mm circular filter paper piece is attached on the above-mentioned plate containing bacterium made, and each culture dish (diameter 90mm) sticks 3 and dipped same rubs
The filter paper (filter paper is spaced identical as far as possible) of your concentration of test object methanol solution, using 50% methanol solution as blank control.
Processed plate containing bacterium is placed in 37 DEG C of insulating boxs cultivate for 24 hours, using crossing method measure colony diameter, and according to
Lower formula calculates inhibiting rate (IR).
Using inhibiting rate (IR) to the logarithm (log of the concentration (μM) of the first morpholine ketone compounds in combined system
(c)) it maps, and carries out linear regression with Excel, assembly when generating specific depression effect (fa) is extrapolated according to regression equation
The concentration of a morpholine ketone compounds, i.e. IC in beingfa(mixA), further according to the first morpholine ketone compounds and second in combined system
The molar ratio of morpholine ketone compounds, when extrapolating fa depression effect in combined system the second morpholine ketone compounds concentration,
That is ICfa(mixB)。
The connection of the combined system containing the first morpholine ketone compounds and the second morpholine ketone compounds is calculated according to the following formula
Share medicine index CI.
As CI < 1, synergistic effect is indicated, and the smaller representative synergistic effect of CI is stronger, the results are shown in Table 1.
Table 1
Embodiment 1 contains the piece for the combined system being made of the first morpholine ketone compounds and the second morpholine ketone compounds
The preparation of agent
Prescription
Preparation method
The combined system and diluent, lubricant for taking recipe quantity, after being sufficiently mixed, tabletting, both.
Embodiment 2 contains the glue for the combined system being made of the first morpholine ketone compounds and the second morpholine ketone compounds
The preparation of wafer
Prescription
Preparation method
The combined system, diluent and lubricant for taking recipe quantity, be sufficiently mixed rear filling capsule to get.
Embodiment 3 contains for the combined system being made of the first morpholine ketone compounds and the second morpholine ketone compounds
The preparation of granula
Prescription
Preparation method
The combined system, diluent and lubricant for taking recipe quantity, after being sufficiently mixed dispense to get.
Claims (10)
1. containing the first morpholine ketone compounds and the second morpholone by different and molar ratio in 0.01~100 range
The composition for the combined system that class compound is constituted, which is characterized in that the first morpholine ketone compounds and the second morpholone
Class compound is selected from one of following compound respectively:
2. composition according to claim 1, which is characterized in that the combined system is one in following combined system
Kind:
By molar ratio in 0.5~1 rangeWith
The combined system of composition,
By molar ratio in 25~75 rangesWith
The combined system of composition,
By molar ratio in 0.25~0.75 rangeWithThe combined system of composition,
By molar ratio in 0.75~25 rangeWithThe combined system of composition,
By molar ratio in 0.01~0.25 rangeWithThe combined system of composition,
By molar ratio in 50~100 rangesWith
The combined system of composition,
By molar ratio in 25~75 rangesWithThe combined system of composition,
By molar ratio in 0.25~0.75 rangeWithThe combined system of composition,
By molar ratio in 0.01~0.25 rangeWithThe combined system of composition,
By molar ratio in 75~100 rangesWithIt constitutes
Combined system,
By molar ratio in 50~100 rangesWithThe combined system of composition,
By molar ratio in 0.5~1 rangeWithThe combined system of composition,
By molar ratio in 0.01~0.5 rangeWithThe combined system of composition,
By molar ratio in 0.25~0.75 rangeWithThe combined system of composition,
By molar ratio in 50~100 rangesWithIt constitutes
Combined system,
By molar ratio in 25~75 rangesWithThe combined system of composition,
By molar ratio in 0.01~50 rangeWithStructure
At combined system,
By molar ratio in 0.25~0.75 rangeWithThe combined system of composition.
3. composition according to claim 2, which is characterized in that the combined system is one in following combined system
Kind:
By molar ratio in 0.5~1 rangeWith
The combined system of composition,
By molar ratio in 25~75 rangesWith
The combined system of composition,
By molar ratio in 0.25~0.75 rangeWithThe combined system of composition,
By molar ratio in 0.75~25 rangeWithThe combined system of composition,
By molar ratio in 0.01~0.25 rangeWithThe combined system of composition,
By molar ratio in 50~100 rangesWith
The combined system of composition,
By molar ratio in 25~75 rangesWithThe combined system of composition,
By molar ratio in 0.25~0.75 rangeWithThe combined system of composition,
By molar ratio in 0.01~0.25 rangeWithThe combined system of composition.
4. composition according to claim 3, which is characterized in that the combined system is one in following combined system
Kind:
It is 0.75 by molar ratioWithThe group of composition
Zoarium system,
It is 50 by molar ratioWithThe combination of composition
System is 0.5 by molar ratioWithIt constitutes
Combined system,
It is 1 by molar ratioWithThe combination of composition
System is 0.01 by molar ratioWith
The combined system of composition,
It is 75 by molar ratioWithThe combination of composition
System,
It is 50 by molar ratioWithIt constitutes
Combined system,
It is 0.5 by molar ratioWithStructure
At combined system,
It is 0.01 by molar ratioWithThe combined system of composition.
5. the oral drug preparation containing composition according to claim 1~any one of 4.
6. oral drug preparation according to claim 5, which is characterized in that the dosage form of the preparation is selected from tablet, capsule
One of agent and granule.
7. preparation according to claim 6, which is characterized in that the preparation further contains diluent and lubricant.
8. preparation according to claim 7, which is characterized in that the diluent be selected from pregelatinized starch, starch, dextrin,
One of sucrose, microcrystalline cellulose, sorbierite, mannitol, lactose, calcium sulfate, calcium monohydrogen phosphate and calcium phosphate；The lubrication
Agent be more preferably selected from sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, paraffin oil, paraffin, glycerin monostearate,
Monopalmitin, sodium chloride, DL-leucine, sldium lauryl sulfate, magnesium laurylsulfate, polyethylene glycol, gathers sodium acetate
One of ethylene oxide monostearate and Brij30.
9. composition according to claim 1~any one of 4 is in preparing the drug for treating bacterial infection disease
Purposes.
10. purposes according to claim 9, which is characterized in that the bacterial infection disease is by selected from Escherichia coli, copper
Green pseudomonad, methicillin sensitive S staphylococcus, methicillin-resistant S staphylococcus, pneumonia streptococcus
Bacterium, vancomycin sensitive enterococcus, vancomycin-resistant enterococcus, Acinetobacter bauamnnii, proteus mirabilis and pneumonia
Disease caused by one of klebsiella bacterium infection.
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|---|---|---|---|
| CN201811562463.1A CN109481445A (en) | 2018-12-19 | 2018-12-19 | Composition containing morpholine ketone compounds |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811562463.1A CN109481445A (en) | 2018-12-19 | 2018-12-19 | Composition containing morpholine ketone compounds |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060887A1 (en) * | 2003-01-07 | 2004-07-22 | Bayer Healthcare Ag | Method for producing 5-chloro-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide |
| CN106432218A (en) * | 2015-12-18 | 2017-02-22 | 重庆植恩药业有限公司 | Rivaroxaban impurities and preparing method and application thereof |
-
2018
- 2018-12-19 CN CN201811562463.1A patent/CN109481445A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060887A1 (en) * | 2003-01-07 | 2004-07-22 | Bayer Healthcare Ag | Method for producing 5-chloro-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide |
| CN106432218A (en) * | 2015-12-18 | 2017-02-22 | 重庆植恩药业有限公司 | Rivaroxaban impurities and preparing method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| R. AGARWAL等: "Synthesis and Antimicrobial Activity of Fatty 2-Morpholinones Prepared from Epoxy Fatty Acid Methyl Esters", 《JAOCS》 * |
| 蔡正艳等: "利伐沙班有关物质的合成及结构确定", 《中国医药工业杂志》 * |
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