CN104059082B - Nitroimidazole heterocycle compound and the application in preparation treatment tubercular drugs thereof - Google Patents
Nitroimidazole heterocycle compound and the application in preparation treatment tubercular drugs thereof Download PDFInfo
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Abstract
The present invention relates to the novel nitroimidazole Hete rocyclic derivatives of a class and the purposes in preparation treatment tubercular drugs thereof.The nitroimidazole Hete rocyclic derivatives of the present invention its there is double action mechanism, protein synthesis and the synthesis of cell wall mycolic acid of mycobacterium tuberculosis can be suppressed, to causing pathogen mycobacterium tuberculosis lungy to have the strongest activity, and bioavailability is higher.
Description
Technical field
The present invention relates to nitroimidazole Hete rocyclic derivatives and the purposes in preparation treatment tubercular drugs thereof.Background technology
Tuberculosis (tuberculosis, TB) it is to be infected, by single pathogen mycobacterium tuberculosis (Mycobacteriumtuberculosis), the chronic infectious disease caused, mainly involve lung, it is the single disease causing death toll most in infectious disease, is also the most common chance infectious disease relevant to acquired immune deficiency syndrome (AIDS).So far, tuberculotherapy medicine has been applied to clinical more than 40 year, multidrug resistance tuberculosis and extensive drug resistance tuberculosis occurs, and therefore tuberculosis has become the significant threat of human health and life security.
The first-line drug of antituberculosis therapy includes rifampicin and isoniazid etc. at present, use generation long-term, that regular, therapeutic alliance can prevent multidrug resistance bacterial strain, but these adverse effectes are many, bactericidal action is not strong, the course for the treatment of must use more than 6 months, patient compliance is poor.When using two wires antituberculotics such as capreomycin and ethionamide etc. after conventional therapy failure, but these adverse effectes are relatively big, and treatment time longer (18～24 months), both expensive, cure rate is the lowest.The tuberculosis chemotherapy being made up of these lines and Second line Drug can cause serious toxicity and Drug resistance.Therefore, novel drugs lungy is treated in exploitation, and tool is had very great significance by the newtype drug particularly having the antagonistic drug bacterial strain of novel mechanism active.
Summary of the invention
The technical problem to be solved is to provide a kind of new nitroimidazole heterocycle compound to mycobacterium tuberculosis with the strongest activity.
For solving above technical problem, the present invention adopts the following technical scheme that:
A kind of nitroimidazole heterocycle compound with logical formula (I), its officinal salt, hydrate, prodrug or the metabolite that metabolism is formed in any form
Wherein:
R1Represent H, CH2F、CHF2、CF3、CnH2n+1、CnH2n-1、NO2、F、Cl、Br、I、CN、OH、OCnH2n+1、OCnH2n-1、SH、SCnH2n+1、SCnH2n-1、NH2、NHCnH2n+1、NHCnH2n-1、N(CnH2n+1)(CnH2n+1)、N(CnH2n+1)(CnH2n-1)、N(CnH2n-1)(CnH2n-1)、NH(COCnH2n+1) or NH (COCnH2n-1)；
R2Represent H, CH2F、CHF2、CF3、CnH2n+1Or CnH2n-1；
R3Represent H, CnH2n+1、CnH2n-1、CHO、COCnH2n+1、COCnH2n-1、COOCnH2n+1、COOCnH2n-1、NCONH2、CONH(CnH2n+1) or CONH (CnH2n-1)；
R4Represent CH2F、CHF2Or CF3；
A represents O, S, NH, NCnH2n+1、NCnH2n-1、NCOCnH2n+1、NCOCnH2n-1、NCOOCnH2n+1、NCOOCnH2n-1、NCONH2、NCONH(CnH2n+1) or NCONH (CnH2n-1)；
B and E represents C independentlymH2m-4、CnH2n、CqH2q-2Or CpH2p-8；
D is CmH2m-4、CnH2n、CqH2q-2、CpH2p-8、CmH2m-4C6H4O、CnH2nC6H4O、CqH2q-2C6H4O、CpH2p-8C6H4O、CmH2m-4C5H3NO、CnH2nC5H3NO、CqH2q-2C5H3NO、CpH2p-8C5H3NO、CmH2m-4C4H2N2O、CnH2nC4H2N2O、CqH2q- 2C4H2N2Or CpH2p-8C4H2N2O；
W, M, Y and Z represent C-H, N, C-C independentlynH2n+1、C-CnH2n、C-CnH2n-1、C-OH、C-OCnH2n+1、C-OCnH2n-1、C-OCnH2n、C-C6H5、C-CnH2nC6H5、C-OC6H5、C-OCnH2nC6H5、C-C5H4N、C-CnH2nC5H4N、C-OC5H4N、C-OCnH2nC5H4N、C-C4H3N2、C-CnH2nC4H3N2、C-OC4H3N2、C-OCnH2nC4H3N2、C-CN、C-NO2、C-CH2F、C-CHF2、C-CF3、C-OCH2F、C-OCHF2、C-OCF3, C-F, C-Cl, C-Br or C-I；
Above-mentioned n is the integer more than zero；M is the integer more than or equal to 3；P is the integer more than or equal to 7；Q is the integer more than or equal to 3；
In formula (I), when W, M, Y and Z are not N, R4For CH2F or CHF2；Described nitroimidazole heterocycle compound, in the metabolite of its officinal salt, hydrate, prodrug and metabolism formation in any form, the hydrogen of commutativity can be replaced by deuterium.
Preferably, in formula I, A is O or S, R1、R2、R3、R4, B, C, D, W, M, Y and Z be defined as above.It is further preferred that in formula I, A is O or S, E is CnH2n, R1For H, R2、R3、R4, B, D, W, M, Y and Z be defined as above.Preferably, above-mentioned n takes the integer between 1-12, and m is the integer between 3-20, and m is more preferably 3,4 or 5；P is the integer between 7-20, more preferably 7,8 or 9；Q is the integer between 3-20.
According to a specific aspect, in formula I, A be O, E be CH2, R1For H, R2For H, now its structure is as shown in the formula (II):
In formula II, R3、R4, B, D, W, M, Y and Z be defined as above；
In formula II, when W, M, Y and Z are not N, R4For CH2F or CHF2。
Further, in formula (II), W and Y is CH, and now its structure is as shown in the formula (III):
In formula III, R3、R4, B, M and Z be defined as above；
In formula III, when M and Z is not N, R4For CH2F or CHF2。
Preferably, in formula (III), B is CH2、CH(CH3)、CH(CH2CH3)、CH(CH2CH2CH3) or CHCH (CH3)2。
Preferably, in formula (III), R3Represent H, CH3、CH2CH3、CH2CH2CH3、CHO、COCnH2n+1, wherein n is the integer between 1～6.
Preferably, in formula (III), D is CH2、CH(CH3)、CH(CH2CH3)、CH(CH2CH2CH3)、CHCH(CH3)2Or CH2C6H4。
Preferably, in formula (III), M, Z independently be C-H, N, C-CnH2n+1、C-CnH2n、C-CnH2n-1、C-OH、C-OCnH2n+1、C-OCnH2n-1、C-OCnH2n、C-OC6H5、C-OCnH2nC6H5、C-CN、C-NO2、C-CH2F、C-CHF2、C-CF3、C-OCH2F、C-OCHF2、C-OCF3、C-F、C-Cl、C-Br。
According to the present invention, some representational compounds have compound (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip),
(Iq), (Ir), (Is), (It) and (Iu).
The synthetic method that the above-mentioned compound of the present invention can use organic synthesis field conventional obtains.
In addition, the present invention relates particularly to above-mentioned nitroimidazole heterocycle compound, its officinal salt, hydrate, the metabolite that prodrug or in any form metabolism are formed purposes in the medicine of the indication relevant with mycobacterium tuberculosis protein matter and cell wall mycolic acid complex functionality is treated in preparation.
It is particularly preferred that the described indication relevant to mycobacterium tuberculosis protein matter and cell wall mycolic acid complex functionality is mainly tuberculosis.
The present invention provides the pharmaceutical composition of a kind of indication relevant with mycobacterium tuberculosis protein matter and cell wall mycolic acid complex functionality for treatment the most especially, and its effective ingredient is including at least above-mentioned nitroimidazole heterocycle compound.
Further, the effective ingredient of described pharmaceutical composition can also comprise the other medicines in addition to nitroimidazole heterocycle compound of the present invention.
According to the present invention, described compound, it not only includes certain single compound form, also includes that various structures meets the form of mixtures of the compound of formula requirement, and the different isomer form of same compound such as racemic modification, enantiomer, diastereomer etc..Described officinal salt includes but not limited to hydrochlorate, phosphate, sulfate, acetate, maleate, mesylate, benzene sulfonate, benzoic acid salt, toluenesulfonate, succinate, fumarate, fumarate, tartrate, gallate, citrate etc..It is described that " prodrug with the compound of logical formula I " refers to a kind of material, after using suitable method to use, can carry out metabolism or chemical reaction and be transformed at least one compound or its salt of structure formula I in subject.
Due to the enforcement of above technical scheme, the present invention compared with prior art has the advantage that
The compound that the present invention provides is novel nitroimidazole heterocycle compound, and it has double action mechanism, can suppress the protein synthesis of mycobacterium tuberculosis, suppress again the synthesis of cell wall mycolic acid, have the strongest activity to mycobacterium tuberculosis.Additionally, the compound first pass effect of the present invention is less, effective bioavailability is higher, has using dosage when treating the indication relevant with mycobacterium tuberculosis protein matter and cell wall mycolic acid complex functionality few, the advantage that side effect is less.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the present invention is not limited to following example.
Embodiment 1
Compound Ib, compound Ic, compound Ik, compound Im, compound In, compound Io, compound Ip, compound Iq, compound Ir, compound Is, compound It and compound Iu, its chemical structural formula is as follows:
Above compound can be obtained by following synthetic route:
One concrete preparation method is as follows:
(1), by 2; 4-Nitroimidazole (compound 2) joins in R-dehydration glycerol butyrate (compound 7), under nitrogen protection, adds appropriate DMF; it is warming up to 50-60 DEG C react 10-20 hour; until compound 2 disappears, adding a large amount of water, methyl tertiary butyl ether(MTBE) extracts; washing; it is concentrated to give faint yellow jelly, is compound 3[productivity 70%, ESI-MS [MH]+: 303.0930].
(2), compound 3 is dissolved in dichloromethane, addition 3,4-dihydro-2H-pyrans (DHP, 2.0eq.), pyridinium p-toluenesulfonate (PPTS, 0.3eq.), reaction is stirred at room temperature overnight to raw material disappearance.Organic facies is washed 2 times, and anhydrous sodium sulfate concentrates removing solvent after drying and obtains product, is compound 4[productivity 85%, and ESI-MS [MH]+: 387.1510], it is directly used in next step reaction.
(3), step (2) gained compound 4 is dissolved in methanol, adds 1.0eq.Cs in 0 DEG C2CO3, react 1-3 hour, filter, concentrated mother liquor, obtain faint yellow solid by hexane and re-crystallizing in ethyl acetate, be compound 5[productivity 60%, ESI-MS [MH]+: 270.1090].
(4) methanol, by 5.0 g of compound 5 it is dissolved in, room temperature dropping acidic alcohol (1.0eq.), stirring reaction 1h, concentrating under reduced pressure solvent, obtain faint yellow solid, be compound 8[productivity: 27%, ESI-MS [M+H]+: 186.0506], it is directly used in next step reaction.
(5), in step (4) gained compound 8, it is slowly added dropwise MsCl(3.0eq.), reaction 15h is stirred at room temperature, reacts complete, concentration is spin-dried for obtaining yellow mixture, adds water making beating 2h, filters, it is dried, obtains faint yellow solid and be compound 9[productivity: 87%, ESI-MS [M+H]+: 263.2279].
(6), compound 9 DMF is dissolved, add 12eq.NaN3, and it being warming up to 70 DEG C of reactions 15h, after completion of the reaction dilutes, ethyl acetate extracts, and merges organic facies, washing, is dried, obtains brown solid and be compound 10[productivity: productivity, ESI-MS [M+H] after concentration+: 211.0579].
(7), compound 10 is dissolved in absolute methanol, is sequentially added into triethylamine (5.0eq.), 1,3-dimercaptopropane (5.0eq.), after room temperature reaction 0.5-2h, removal of solvent under reduced pressure, obtain taupe sticky solid and be compound 11, be directly used in next step reaction.
(8) when in the structural formula of target product R be H: by compound 11 DMF dissolve, add 2.5eq. acetic acid, 1.2eq. aromatic aldehyde ArCHO, reenter 2.5eq.NaBH after 20min is stirred at room temperature3CN, room temperature reaction is overnight to raw material disappearance.Adding water and diluted ethyl acetate, stirring layering, aqueous phase is extracted with ethyl acetate 2 times again, merges organic facies, is dried, and concentrates, and rapid column chromatography obtains faint yellow product.
When in the structural formula of target product, R is not H: compound 11 THF is dissolved, add 3.0eq. acetic acid, 1.2eq. arone ArCOR, after 20min is stirred at room temperature, reenter 3.0eq.Ti (O-iPr)4, 1.5h is stirred at room temperature, adds 3.0eq.NaBH3CN, room temperature reaction is overnight to raw material disappearance.Dilute, dichloromethane extracts, and merges organic facies, washing, is dried, concentrates, and rapid column chromatography obtains faint yellow solid product.
The preparation of above-mentioned aromatic aldehyde/ketone (ArCOR) refers to document SperryJB., SutherlandK.Org.ProcessRes.Dev.2011,15,721-725. or document ZhangL., and ZhengJ., HuJ.J.Org.Chem.2006,71,9845-9848. are carried out.Two instantiations are presented herein below.
Example 1: preparation is to 4-difluoro-methoxy benzaldehyde
Take 2g hydroxy benzaldehyde, use DMF/H2O(9:1) mixed liquor dissolves, and adds 1.2eq.K2CO3,2.0eq.NaCO2CF2Cl, room temperature to 100 DEG C reaction 15h or complete to reacting.It is down to room temperature, adds 20%NaOHaq. and regulate pH to 11, add MTBE extraction, merge organic facies, washing, concentrate, be dried, after rapid column chromatography, obtain weak yellow liquid product [2.1g, productivity: 75%]
Example 2: preparation is to 4 '-difluoro-methoxy-4-biphenylcarboxaldehyde
Take 20.0g4 '-hydroxyl-4-biphenylcarboxaldehyde ACN/H2O(1:1) mixed liquor dissolves, and proceeds in tube sealing, adds 36eq.K2CO3,5.0eq.PhCOCF2Cl, room temperature to 80 DEG C reaction 24h.Being down to room temperature, dilute, ethyl acetate extracts, and merges organic facies, washing, concentrates, is dried, obtains faint yellow solid product [8.0g, productivity: 32%] after rapid column chromatography
Take said method to prepare above-mentioned compound Ib～compound Iu, raw material feed intake and the yield of corresponding target product and productivity see table 1.
Table 1
| Target compound | Compound 10 inventory | Target compound yield | Productivity |
| Compound Ib | 300mg | 210mg | 43% |
| Compound Ic | 300mg | 180mg | 36% |
| Compound Ik | 300mg | 280mg | 45% |
| Compound Im | 300mg | 255mg | 45% |
| Compound In | 300mg | 250mg | 42% |
| Compound Io | 300mg | 240mg | 46% |
| Compound Ip | 300mg | 240mg | 46% |
| Compound Iq | 300mg | 280mg | 47% |
| Compound Ir | 300mg | 230mg | 48% |
| Compound Is | 300mg | 200mg | 34% |
| Compound It | 300mg | 200mg | 41% |
| Compound Iu | 300mg | 250mg | 45% |
The target compound obtained has been carried out hydrogen nuclear magnetic resonance1H-NMR and19F-NMR and mass spectrometric measurement, result is summed up as shown in table 2.
Table 2
Embodiment 2
Compound Id, compound If, compound Ii and compound Ij, its chemical structural formula is as follows:
Above compound can be obtained by following synthetic route:
One concrete preparation process is as follows:
(1), by 2,4-Nitroimidazole (compound 2) is dissolved in ethanol, adds 0.067eq.K2CO3After 10min is stirred at room temperature, adding the ethanol solution of 0.33eq. compound 12, room temperature to 75 DEG C is reacted overnight, the most directly concentrates dry solvent, add ethyl acetate solvent, washing, is dried, obtains faint yellow jelly after column chromatography, it is compound 13[productivity: 42%, ESI-MS [M+H]+: 330.2941].
(2), compound 13 is dissolved in dichloromethane, is sequentially added into 3,4-dihydro-2H-pyrans (2.0eq.), 0.3eq.PPTS, is stirred at room temperature reaction and overnight disappears to raw material, wash, being dried, the product that organic facies is concentrated to give is compound 14, is directly used in next step reaction.
(3), compound 14 is dissolved in THF, the THF solution of 4.0eq.1MTBAF is dripped under room temperature, finish, at room temperature stirring reaction 1h, then be warming up to 70 DEG C of reaction 16h, concentrate, add acetic acid ethyl dissolution, washing, organic facies concentrates after drying, after rapid column chromatography, obtain faint yellow solid be compound 15[productivity: 44%, ESI-MS [M+H]+: 298.1395].
(4), by compound 15 it is dissolved in methanol, room temperature dropping ethanol solution hydrochloride (1.0eq.), stirring reaction 1h, concentrating under reduced pressure solvent, obtains faint yellow solid, be compound 16, be directly used in next step.
(5), compound 16 dissolves with methanol, add triethylamine (3.0eq.), and be slowly added dropwise MsCl(3.0eq.), reaction 15h is stirred at room temperature, react complete, it is spin-dried for obtaining yellow mixture, adds water making beating 2h, filter, it is dried, obtain faint yellow solid, be compound 17[productivity: 95%, ESI-MS [M+H]+: 292.0593].
(6), compound 17 DMF is dissolved, add 12eq.NaN3, and it being warming up to 70 DEG C of reactions 15h, after completion of the reaction dilutes, ethyl acetate extracts, and merges organic facies, washing, is dried, obtains brown solid after concentration, be compound 18[productivity: 58%, ESI-MS [M+H]+: 239.0882].
(7), compound 18 be dissolved in DMF, be sequentially added into triethylamine (5.0eq.), 1,3-dimercaptopropane (5.0eq.), after room temperature reaction 1-3h, removal of solvent under reduced pressure, obtain taupe viscous solution 19, be directly used in next step.
(8), when in target product structural formula R be H: viscous solution 19 DMF dissolve, add 2.5eq. acetic acid, 1.2eq. aromatic aldehyde ArCHO, reenter 2.5eq.NaBH after 20min is stirred at room temperature3CN, room temperature reaction is overnight to raw material disappearance.Adding water and diluted ethyl acetate, stirring layering, aqueous phase is extracted with ethyl acetate 2 times again, merges organic facies, is dried, and concentrates, and rapid column chromatography obtains faint yellow product.
When R is not that H: viscous solution 19 THF dissolves in target product structural formula, adds 3.0eq. acetic acid, 1.2eq. ketone ArCOR, after 20min is stirred at room temperature, reenter 3.0eq.Ti (O-iPr)4, 1.5h is stirred at room temperature, adds 3.0eq.NaBH3CN, room temperature reaction is overnight to raw material disappearance.Dilute, dichloromethane extracts, and merges organic facies, washing, is dried, concentrates, and rapid column chromatography obtains faint yellow product.
Take said method to prepare above-mentioned compound Id, compound If, compound Ii and compound Ij, raw material feed intake and the yield of corresponding target product and productivity see table 3.
Table 3
| Target compound | Compound 18 inventory | Target compound yield | Productivity |
| Compound Id | 300mg | 160mg | 34% |
| Compound If | 300mg | 200mg | 43% |
| Compound Ii | 300mg | 260mg | 46% |
| Compound Ij | 300mg | 240mg | 41% |
The target compound obtained has been carried out hydrogen nuclear magnetic resonance1H-NMR and19F-NMR and mass spectrometric measurement, result is summed up as shown in table 4.
Table 4
Embodiment 3
Compound Ie, its chemical structural formula is as follows:
The preparation method of Formulas I e compound is as follows: 400mg compound Ic adds DMF and dissolves, add 2.5eq. acetic acid, 2.5eq. paraformaldehyde, 2.5eq.NaBH3CN, in room temperature reaction 15h, reacts complete, adds water, and ethyl acetate extracts, and merges organic layer, washing, is dried, is spin-dried for, and rapid column chromatography obtains product, is compound Ie[285mg, productivity: 69%].
Embodiment 4
Compound Ig per, its chemical structural formula is as follows:
The preparation method of Compound Ig per is as follows: 300mg compound If adds DMF and dissolves, add 2.5eq. acetic acid, 2.5eq. paraformaldehyde, 2.5eq.NaBH3CN, in room temperature reaction 15h, reacts complete, adds water, and ethyl acetate extracts, and merges organic layer, washing, is dried, is spin-dried for, and rapid column chromatography obtains product [200mg, productivity: 64%].
Embodiment 5
Compound Ih, its chemical structural formula is as follows:
The preparation method of compound Ih is as follows: by 2.0eq. acetic anhydride, 2.0eq. anhydrous formic acid mixes, 0.5h is stirred at room temperature, 100mg Formulas I f compound adding THF dissolve, reactant liquor in instillation, in 0 DEG C～room temperature reaction 1h, reacting complete, add water, ethyl acetate extracts, merge organic layer, washing, be dried, it is spin-dried for, rapid column chromatography obtains product, is compound Ib[90mg, productivity: 84%].
Gained compound Ie, Compound Ig per and compound Ih thing have been carried out hydrogen nuclear magnetic resonance1H-NMR and19F-NMR and mass spectrometric measurement, result is summed up as shown in table 6.
Table 6
Drug effect and pharmacokinetics test
One, Compound ira vitro suppression mycobacterium tuberculosis active testing:
1, test method
Mycobacterium tuberculosis type strain H37Rv is from DSMZ of country (ATCC27294), mycobacterium tuberculosis clinical separation strain B2[substance of medicines-resistant branched tubercle bacillus (MDRTB)] and the extensive Drug-Resistant Mycobacterium tuberculosis of B29[(XDRTB)] it is clinically separated preservation from Shanghai Pulmonary Hospital.Strain subject is proceeded to Middlebrook7H9 fluid medium, cultivate 2 weeks in 37 DEG C, draw cultivation bacterium solution a little, it is placed in 4mL fluid medium, addition diameter 2～3mm sterile glass beads 10～20, vibrates 20～30 seconds, quiescent setting 10～20 minutes, draw bacteria suspension supernatant, adjust turbid to 1 Maxwell unit of ratio with fluid medium, be equivalent to 1mg/mL standby.Target compound DMSO dissolves, then is diluted to required experimental concentration with fluid medium.During detection, respectively take above-mentioned solution title compound 100 μ L and be added in 96 hole microwell plates, add 10-3The bacterium solution 100 μ L of mg/mL concentration, makes target compound concentration reach the final concentration arranged.37 DEG C of cultivations, the object observing compound minimum inhibitory concentration to mycobacterium tuberculosis type strain H37Rv.
2, result of the test
Table 7 summarizes target compound to mycobacterium tuberculosis type strain H37Rv inhibitory activity experimental result.Result display target compound (Ib, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Im, In, Io, Ip, Iq, Is and Iu) has very high inhibition effect to H37Rv type strain.
Simultaneously, selecting partial target compound (Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Im, In, Io, Iq and Is) to determine substance of medicines-resistant branched tubercle bacillus (MDRTB) and the inhibitory action of extensive Drug-Resistant Mycobacterium tuberculosis (XDRTB), result of the test is summed up in table 8.Result shows that all target compounds have the strongest or a certain degree of inhibitory action to substance of medicines-resistant branched tubercle bacillus and extensive Drug-Resistant Mycobacterium tuberculosis.
Table 7
| Target compound | MIC(μg/mL) |
| Compound Ib | 0.0625 |
| Compound Ic | 0.125 |
| Compound Id | 0.03125 |
| Compound Ie | 0.03125 |
| Compound If | 0.0078 |
| Compound Ig per | 0.0078 |
| Compound Ih | 0.03125 |
| Compound Ii | 0.015 |
| Compound Ij | 0.015 |
| Compound Ik | 0.015 |
| Compound Im | 0.03125 |
| Compound In | 0.03125 |
| Compound Io | 0.0078 |
| Compound Ip | 0.0625 |
| Compound Iq | 0.00195 |
| Compound Ir | 0.25 |
| Compound Is | 0.03125 |
| Compound It | 0.125 |
| Compound Iu | 0.0625 |
Table 8
| Target compound | MIC(μg/mL)(MDRTB) | MIC(μg/mL)(XDRTB) |
| Compound Id | 0.125 | 0.03125 |
| Compound Ie | 0.25 | 0.0625 |
| Compound If | 0.0625 | 0.03125 |
| Compound Ig per | 0.0625 | 0.015 |
| Compound Ih | 0.25 | 0.125 |
| Compound Ii | 0.125 | 0.0625 |
| Compound Ij | 0.0625 | 0.0625 |
| Compound Ik | 0.0625 | 0.0625 |
| Compound Im | 0.0625 | 0.0625 |
| Compound In | 0.125 | 0.125 |
| Compound Io | 0.03125 | 0.03125 |
| Compound Iq | 0.0625 | 0.015 |
| Compound Is | 0.0078 | 0.0078 |
Two, pharmacokinetic experiment
1, experimental technique:
Laboratory animal: CD-1 mice, male, 6～7 weeks；Body weight: 20～25g；
Test sample is prepared: test compound is configured to 0.2mg/mL(be intravenously administrable with) and 1.0mg/mL(be oral administration use), stand-by.Route of administration: oral/vein.It is administered capacity and frequency: 5mL/kg, single-dose.
Sample collecting: gather blood, 3 animals of each time point according to following time point, take whole blood about 0.5-1.0mL.After being administered, 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h take blood.All animals all implement euthanasia after completing test.
2, sample analysis and result
Sample analysis: use LC-MS/MS method to detect gathering sample.Use INSTRUMENT MODEL is SHIMADZU20A-API4000.
Pharmacokinetic data Analysis: using WinNolin be fitted gained plasma drug concentration data according to non-compartment model method and calculate, partial results is summarised in table 9.
The partial target compound medicine kinetic parameter that table 9 calculates according to non-compartment model method
Result of the test in CD-1 mice shows that the compounds of this invention has a good pharmacokinetic characteristic, low including clearance rate, oral absorption good and the attribute such as long half time.
Above example is only representational.Visible by above-described embodiment, the compound of the present invention has the strongest activity to mycobacterium tuberculosis, and first pass effect is less, and effective bioavailability is high, has using dosage when treating tuberculosis and relevant indication few, the advantage that side effect is little.The compound of the present invention can also combine with different types of pharmaceutical salts and make oral formulations (tablet or capsule etc.).The tablet made with the compounds of this invention or capsule can be taken one or more times daily.The compounds of this invention also can combine with other its medicines and make compound preparation, or (include but not limited to following medicine: isoniazid with other drug, rifampicin, pyrazinamide, ethambutol, Moxifloxacin, Bedaquiline, PA-824, rifapentine, rifabutin, streptomycin, kanamycin, amikacin, Gatifloxacin, levofloxacin, ofloxacin, ciprofloxacin, capreomycin, ethionamide, cycloserine, para-aminosalicylic acid, thiacetazone, clarithromycin, clofazimine, amoxicillin-clavulanic acid, imipenum, meropenem, viomycin, terizidone, clofazimine, Delamanid, AZD5847, Sutezolid, and SQ-109) drug combination clinically.
Above-described embodiment only for technology design and the feature of the present invention are described, its object is to allow person skilled in the art will appreciate that present disclosure and to implement according to this, can not limit the scope of the invention with this.All equivalence changes made according to spirit of the invention or modification, all should contain within protection scope of the present invention.
Claims (4)
1. a nitroimidazole heterocycle compound is or/and its officinal salt, it is characterised in that: described compound is the one that formula (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and formula (Iu) represent:
2. nitroimidazole heterocycle compound described in claim 1 is or/and its officinal salt purposes in the medicine of the preparation treatment indication relevant with mycobacterium tuberculosis protein matter and cell wall mycolic acid complex functionality.
Purposes the most according to claim 2, it is characterised in that: the described indication relevant to mycobacterium tuberculosis protein matter and cell wall mycolic acid complex functionality is tuberculosis.
4. the pharmaceutical composition for the treatment indication relevant with mycobacterium tuberculosis protein matter and cell wall mycolic acid complex functionality, it is characterised in that: the effective ingredient of described pharmaceutical composition includes at least the nitroimidazole heterocycle compound described in claim 1 or/and its officinal salt.
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