CN104059082A - Nitroimidazole heterocyclic compound and application of nitroimidazole heterocyclic compound in preparation of medicine for treating tuberculosis - Google Patents

Nitroimidazole heterocyclic compound and application of nitroimidazole heterocyclic compound in preparation of medicine for treating tuberculosis Download PDF

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CN104059082A
CN104059082A CN201310091695.4A CN201310091695A CN104059082A CN 104059082 A CN104059082 A CN 104059082A CN 201310091695 A CN201310091695 A CN 201310091695A CN 104059082 A CN104059082 A CN 104059082A
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compound
formula
nitroimidazole
heterocyclic compound
prodrug
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CN104059082B (en
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殷建明
车大庆
高红军
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METABOMICS Inc
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METABOMICS Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

The invention relates to a novel nitroimidazole heterocyclic compound and an application of the nitroimidazole heterocyclic compound in preparation of a medicine for treating tuberculosis. The nitroimidazole heterocyclic compound of the present invention has dual function mechanism, can inhibit the protein synthesis of tuberculosis mycobacterium and synthesis of cell wall mycolic acid, has strong activity on pathogen tuberculosis mycobacterium capable of causing tuberculosis, and has high bioavailability.

Description

Nitroimidazole heterocyclic compound and the application in preparation treatment tuberculosis medicine thereof
Technical field
The present invention relates to nitroimidazole Hete rocyclic derivatives and the purposes in preparation treatment tuberculosis medicine thereof.Background technology
Tuberculosis (tuberculosis, TB) be to infect by single pathogenic agent mycobacterium tuberculosis (Mycobacterium tuberculosis) chronic infectious disease causing, mainly involve lung, being singlely in transmissible disease to cause the disease that death toll is maximum, is also the most common opportunistic infection disease relevant to acquired immune deficiency syndrome (AIDS).So far, tuberculotherapy medicine has been applied to clinical more than 40 years, occur multidrug resistance tuberculosis and extensive resistance tuberculosis, so tuberculosis has become the significant threat of human health and life security.
The first-line drug of antituberculosis therapy comprises Rifampin and vazadrine etc. at present, adopt generation long-term, that regular, combination therapy can prevent multidrug resistance bacterial strain, yet these adverse drug reactions are many, germicidal action is strong, must use more than 6 months the course for the treatment of, patient compliance is poor.After conventional treatment failure, can use such as capromycin and ethionamide etc. of two wires antitubercular agent, yet these adverse drug reactions are larger, treatment time longer (18～24 months), both expensive, curative ratio is also lower.The tuberculosis chemotherapy consisting of these lines and Second line Drug can cause serious toxicity and resistance.Therefore, exploitation treatment novel drugs lungy, the activated newtype drug of antagonistic drug bacterial strain tool particularly with novel mechanism has very great significance tool.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind ofly new has very strong active nitroimidazole heterocyclic compound to mycobacterium tuberculosis.
For solving above technical problem, the present invention takes following technical scheme:
A nitroimidazole heterocyclic compound with general formula (I), its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form
Wherein:
R 1represent H, CH 2f, CHF 2, CF 3, C nh 2n+1, C nh 2n-1, NO 2, F, Cl, Br, I, CN, OH, OC nh 2n+1, OC nh 2n-1, SH, SC nh 2n+1, SC nh 2n-1, NH 2, NHC nh 2n+1, NHC nh 2n-1, N (C nh 2n+1) (C nh 2n+1), N (C nh 2n+1) (C nh 2n-1), N (C nh 2n-1) (C nh 2n-1), NH (COC nh 2n+1) or NH (COC nh 2n-1);
R 2represent H, CH 2f, CHF 2, CF 3, C nh 2n+1or C nh 2n-1;
R 3represent H, C nh 2n+1, C nh 2n-1, CHO, COC nh 2n+1, COC nh 2n-1, COOC nh 2n+1, COOC nh 2n-1, NCONH 2, CONH (C nh 2n+1) or CONH (C nh 2n-1);
R 4represent CH 2f, CHF 2or CF 3;
A represents O, S, NH, NC nh 2n+1, NC nh 2n-1, NCOC nh 2n+1, NCOC nh 2n-1, NCOOC nh 2n+1, NCOOC nh 2n-1, NCONH 2, NCONH (C nh 2n+1) or NCONH (C nh 2n-1);
B and E represent C independently mh 2m-4, C nh 2n, C qh 2q-2or C ph 2p-8;
D is C mh 2m-4, C nh 2n, C qh 2q-2, C ph 2p-8, C mh 2m-4c 6h 4o, C nh 2nc 6h 4o, C qh 2q-2c 6h 4o, C ph 2p-8c 6h 4o, C mh 2m-4c 5h 3nO, C nh 2nc 5h 3nO, C qh 2q-2c 5h 3nO, C ph 2p-8c 5h 3nO, C mh 2m-4c 4h 2n 2o, C nh 2nc 4h 2n 2o, C qh 2q-2c 4h 2n 2or C ph 2p-8c 4h 2n 2o;
W, M, Y and Z represent C-H, N, C-C independently nh 2n+1, C-C nh 2n, C-C nh 2n-1, C-OH, C-OC nh 2n+1, C-OC nh 2n-1, C-OC nh 2n, C-C 6h 5, C-C nh 2nc 6h 5, C-OC 6h 5, C-OC nh 2nc 6h 5, C-C 5h 4n, C-C nh 2nc 5h 4n, C-OC 5h 4n, C-OC nh 2nc 5h 4n, C-C 4h 3n 2, C-C nh 2nc 4h 3n 2, C-OC 4h 3n 2, C-OC nh 2nc 4h 3n 2, C-CN, C-NO 2, C-CH 2f, C-CHF 2, C-CF 3, C-OCH 2f, C-OCHF 2, C-OCF 3, C-F, C-Cl, C-Br or C-I;
Above-mentioned n is greater than zero integer; M is more than or equal to 3 integer; P is more than or equal to 7 integer; Q is more than or equal to 3 integer;
In formula (I), when W, M, Y and Z are all not N, R 4for CH 2f or CHF 2; Described nitroimidazole heterocyclic compound, in the meta-bolites of its pharmacologically acceptable 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, R 1, R 2, R 3, R 4, B, C, D, W, M, Y and Z definition the same.Further preferably, in formula I, A is O or S, and E is C nh 2n, R 1for H, R 2, R 3, R 4, B, D, W, M, Y and Z definition the same.Preferably, above-mentioned n gets the integer between 1-12, and m is the integer between 3-20, and m 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 concrete aspect, in formula I, A is O, and E is CH 2, R 1for H, R 2for H, now its structure is as shown in the formula (II):
In formula II, R 3, R 4, B, D, W, M, Y and Z definition the same;
In formula II, when W, M, Y and Z are all not N, R 4for CH 2f or CHF 2.
Further, in formula (II), W and Y are CH, and now its structure is as shown in the formula (III):
In formula III, R 3, R 4, B, M and Z definition the same;
In formula III, when M and Z are all not N, R 4for CH 2f or CHF 2.
Preferably, in formula (III), B is CH 2, CH (CH 3), CH (CH 2cH 3), CH (CH 2cH 2cH 3) or CHCH (CH 3) 2.
Preferably, in formula (III), R 3represent H, CH 3, CH 2cH 3, CH 2cH 2cH 3, CHO, COC nh 2n+1, wherein n is the integer between 1～6.
Preferably, in formula (III), D is CH 2, CH (CH 3), CH (CH 2cH 3), CH (CH 2cH 2cH 3), CHCH (CH 3) 2or CH 2c 6h 4.
Preferably, in formula (III), M, Z is C-H, N, C-C independently nh 2n+1, C-C nh 2n, C-C nh 2n-1, C-OH, C-OC nh 2n+1, C-OC nh 2n-1, C-OC nh 2n, C-OC 6h 5, C-OC nh 2nc 6h 5, C-CN, C-NO 2, C-CH 2f, C-CHF 2, C-CF 3, C-OCH 2f, C-OCHF 2, C-OCF 3, 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 above-mentioned compound of the present invention can adopt the synthetic method of organic synthesis field routine to obtain.
In addition, the present invention is also particularly related to above-mentioned nitroimidazole heterocyclic compound, its pharmacologically acceptable salt, hydrate, the purposes of the meta-bolites that prodrug or in any form metabolism form in the medicine of the preparation treatment indication relevant with cell walls mycolic acid complex functionality with mycobacterium tuberculosis protein matter.
Particularly preferably, the described indication relevant with cell walls mycolic acid complex functionality to mycobacterium tuberculosis protein matter is mainly tuberculosis.
The present invention also provides a kind of pharmaceutical composition that is used for the treatment of the indication relevant with cell walls mycolic acid complex functionality with mycobacterium tuberculosis protein matter especially, and its effective constituent at least comprises above-mentioned nitroimidazole heterocyclic compound.
Further, the effective constituent of described pharmaceutical composition can also comprise the other medicines except nitroimidazole heterocyclic compound of the present invention.
According to the present invention, described compound, it not only comprises certain single compound form, also comprises that various structures meets the form of mixtures of the compound of general formula requirement, and such as racemic modification, enantiomer, diastereomer etc. of different isomerization bodily form formula of same compound.Described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, maleate, mesylate, benzene sulfonate, benzoic acid salt, toluenesulfonate, succinate, fumarate, fumarate, tartrate, gallate, Citrate trianion etc.It is described that " prodrug with the compound of logical formula I " refers to a kind of material, after adopting appropriate means to use, can in subject, carry out metabolism or chemical reaction and be transformed at least one compound or its salt of structure formula I.
Due to the enforcement of above technical scheme, the present invention compared with prior art tool has the following advantages:
Compound provided by the invention is novel nitroimidazole heterocyclic compound, and it has double action mechanism, can suppress the protein synthesis of mycobacterium tuberculosis, suppresses again the synthetic of cell walls mycolic acid, and mycobacterium tuberculosis is had to very strong activity.In addition, compound first pass effect of the present invention is less, and effectively bioavailability is higher, has using dosage few, the advantage that side effect is less when treating the indication relevant with cell walls mycolic acid complex functionality with mycobacterium tuberculosis protein matter.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the present invention is not limited to following examples.
Embodiment 1
Compounds ib, Compound I c, Compound I k, Compound I m, Compound I n, Compound I o, Compound I p, Compound I q, Compound I r, Compound I s, Compound I t and Compound I u, its chemical structural formula is as follows:
Above compound can obtain by following synthetic route:
A 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; be warming up to 50-60 ℃ of reaction 10-20 hour; until compound 2 disappears, strengthen water gaging, methyl tertiary butyl ether extraction; washing; concentrate and obtain faint yellow gluey thing, be compound 3[productive rate 70%, ESI-MS[MH] +: 303.0930].
(2), compound 3 is dissolved in methylene dichloride, add 3,4-dihydro-2H-pyrans (DHP, 2.0eq.), pyridine tosilate (PPTS, 0.3eq.), stirring at room reaction is spent the night to raw material and is disappeared.Organic phase washing 2 times, concentratedly after anhydrous sodium sulfate drying obtains product except desolventizing, is compound 4[productive rate 85%, ESI-MS[MH]+: 387.1510], be directly used in next step reaction.
(3), step (2) gained compound 4 is dissolved in to methyl alcohol, in 0 ℃, add 1.0eq.Cs 2cO 3, reaction 1-3 hour, filters, and concentrated mother liquor, obtains faint yellow solid by hexane and re-crystallizing in ethyl acetate, is compound 5[productive rate 60%, ESI-MS[MH]+: 270.1090].
(4), by 5.0, digest compound 5 and be dissolved in methyl alcohol, room temperature drips acidic alcohol (1.0eq.), stirring reaction 1h, concentrating under reduced pressure solvent, obtains faint yellow solid, is compound 8[productive rate: 27%, ESI-MS[M+H] +: 186.0506], be directly used in next step reaction.
(5), to slowly dripping MsCl(3.0eq. in step (4) gained compound 8), stirring at room reaction 15h, reacts complete, concentrated being spin-dried for obtains yellow mixture, adds water making beating 2h, filters, dry, obtain faint yellow solid and be compound 9[productive rate: 87%, ESI-MS[M+H] +: 263.2279].
(6), compound 9 use DMF are dissolved, add 12eq.NaN 3, and be warming up to 70 ℃ of reaction 15h, thin up after completion of the reaction, ethyl acetate extraction, merges organic phase, washing is dry, obtains brown solid product after concentrated to be compound 10[productive rate: productive rate, ESI-MS[M+H] +: 211.0579].
(7), compound 10 is dissolved in to anhydrous methanol, add successively triethylamine (5.0eq.), 1,3-dimercaptopropane (5.0eq.), after room temperature reaction 0.5-2h, removal of solvent under reduced pressure, obtains beige sticky solid and is compound 11, is directly used in next step reaction.
(8) in the structural formula of target product, R is H: compound 11 use DMF are dissolved, add 2.5eq. acetic acid, 1.2eq. aromatic aldehyde ArCHO, reenters 2.5eq.NaBH after stirring at room 20min 3cN, room temperature reaction spends the night to raw material and disappears.Add water and ethyl acetate dilution, stir layering, water is extracted with ethyl acetate 2 times again, merges organic phase, dry, and concentrated, rapid column chromatography obtains faint yellow product.
In the structural formula of target product, R is not H: compound 11 use THF are dissolved, add 3.0eq. acetic acid, 1.2eq. arone ArCOR, reenters 3.0eq.Ti (O-iPr) after stirring at room 20min 4, stirring at room 1.5h, adds 3.0eq.NaBH 3cN, room temperature reaction spends the night to raw material and disappears.Thin up, dichloromethane extraction, merges organic phase, and washing is dry, and concentrated, rapid column chromatography obtains faint yellow solid product.
The preparation of above-mentioned aromatic aldehyde/ketone (ArCOR) can reference Sperry J B., Sutherland K.Org.ProcessRes.Dev.2011,15,721-725. or document Zhang L., Zheng J., Hu J.J.Org.Chem.2006,71,9845-9848. carries out.Two specific exampless below.
Example 1: preparation is to 4-difluoro-methoxy phenyl aldehyde
Get 2g p-Hydroxybenzaldehyde, use DMF/H 2o(9:1) mixed solution dissolves, and adds 1.2eq.K 2cO 3, 2.0eq.NaCO 2cF 2cl, room temperature to 100 ℃ reaction 15h or to reacting complete.Be down to room temperature, add 20%NaOH aq. to regulate pH to 11, add MTBE extraction, merge organic phase, washing, concentrated, dry, after rapid column chromatography, obtain weak yellow liquid product [2.1g, productive rate: 75%]
Example 2: preparation is to 4 '-difluoro-methoxy-4-biphenylcarboxaldehyde
Get 20.0g4 '-hydroxyl-4-biphenylcarboxaldehyde ACN/H 2o(1:1) mixed solution dissolves, and proceeds in tube sealing, adds 36eq.K 2cO 3, 5.0eq.PhCOCF 2cl, room temperature to 80 ℃ reaction 24h.Be down to room temperature, thin up, ethyl acetate extraction, merges organic phase, and washing is concentrated, dry, obtains faint yellow solid product [8.0g, productive rate: 32%] after rapid column chromatography
Take aforesaid method to prepare above-mentioned compounds ib～Compound I u, raw material feed intake and the output of corresponding target product and productive rate referring to table 1.
Table 1
Target compound Compound 10 charging capacitys Target compound output Productive rate
Compounds ib 300mg 210mg 43%
Compound I c 300mg 180mg 36%
Compound I k 300mg 280mg 45%
Compound I m 300mg 255mg 45%
Compound I n 300mg 250mg 42%
Compound I o 300mg 240mg 46%
Compound I p 300mg 240mg 46%
Compound I q 300mg 280mg 47%
Compound I r 300mg 230mg 48%
Compound I s 300mg 200mg 34%
Compound I t 300mg 200mg 41%
Compound I u 300mg 250mg 45%
The target compound obtaining has been carried out to hydrogen nuclear magnetic resonance 1h-NMR and 19f-NMR and mass spectrometric measurement, result is summed up as shown in table 2.
Table 2
Embodiment 2
Compound I d, Compound I f, Compound I i and Compound I j, its chemical structural formula is as follows:
Above compound can obtain by following synthetic route:
A concrete preparation process is as follows:
(1), 2,4-Nitroimidazole (compound 2) is dissolved in to ethanol, add 0.067eq.K 2cO 3after stirring at room 10min, the ethanolic soln that adds again 0.33eq. compound 12, room temperature to a 75 ℃ reaction is spent the night, and directly concentrates after completion of the reaction dry solvent, add ethyl acetate solvent, washing, dry, after column chromatography, obtain faint yellow gluey thing, be compound 13[productive rate: 42%, ESI-MS[M+H] +: 330.2941].
(2), compound 13 is dissolved in to methylene dichloride, add successively 3,4-dihydro-2H-pyrans (2.0eq.), 0.3eq.PPTS, stirring at room reaction is spent the night to raw material disappearance, washing, dry, the concentrated product obtaining of organic phase is compound 14, is directly used in next step reaction.
(3), compound 14 is dissolved in to THF, under room temperature, drip the THF solution of 4.0eq.1M TBAF, finish, stirring reaction 1h under room temperature, then be warming up to 70 ℃ of reaction 16h, concentrated, add acetic acid ethyl dissolution, washing, concentrated after organic phase is dry, after rapid column chromatography, obtain faint yellow solid and be compound 15[productive rate: 44%, ESI-MS[M+H] +: 298.1395].
(4), compound 15 is dissolved in to methyl alcohol, room temperature drips ethanol solution hydrochloride (1.0eq.), stirring reaction 1h, and concentrating under reduced pressure solvent, obtains faint yellow solid, is compound 16, is directly used in next step.
(5), compound 16 use dissolve with methanol, add triethylamine (3.0eq.), and slowly drip MsCl(3.0eq.), stirring at room reaction 15h, react complete, be spin-dried for and obtain yellow mixture, add water making beating 2h, filter, dry, obtain faint yellow solid, be compound 17[productive rate: 95%, ESI-MS[M+H] +: 292.0593].
(6), compound 17 use DMF are dissolved, add 12eq.NaN 3, and be warming up to 70 ℃ of reaction 15h, thin up after completion of the reaction, ethyl acetate extraction, merges organic phase, washing is dry, obtains brown solid product after concentrated, is compound 18[productive rate: 58%, ESI-MS[M+H] +: 239.0882].
(7), compound 18 is dissolved in DMF, adds successively triethylamine (5.0eq.), 1,3-dimercaptopropane (5.0eq.), after room temperature reaction 1-3h, removal of solvent under reduced pressure, obtains beige viscous fluid 19, is directly used in next step.
(8), in target product structural formula, R is H: viscous fluid 19 use DMF dissolve, and add 2.5eq. acetic acid, and 1.2eq. aromatic aldehyde ArCHO, reenters 2.5eq.NaBH after stirring at room 20min 3cN, room temperature reaction spends the night to raw material and disappears.Add water and ethyl acetate dilution, stir layering, water is extracted with ethyl acetate 2 times again, merges organic phase, dry, and concentrated, rapid column chromatography obtains faint yellow product.
In target product structural formula, R is not H: viscous fluid 19 use THF dissolve, and add 3.0eq. acetic acid, and 1.2eq. ketone ArCOR, reenters 3.0eq.Ti (O-iPr) after stirring at room 20min 4, stirring at room 1.5h, adds 3.0eq.NaBH 3cN, room temperature reaction spends the night to raw material and disappears.Thin up, dichloromethane extraction, merges organic phase, and washing is dry, and concentrated, rapid column chromatography obtains faint yellow product.
Take aforesaid method to prepare above-mentioned Compound I d, Compound I f, Compound I i and Compound I j, raw material feed intake and the output of corresponding target product and productive rate referring to table 3.
Table 3
Target compound Compound 18 charging capacitys Target compound output Productive rate
Compound I d 300mg 160mg 34%
Compound I f 300mg 200mg 43%
Compound I i 300mg 260mg 46%
Compound I j 300mg 240mg 41%
The target compound obtaining has been carried out to hydrogen nuclear magnetic resonance 1h-NMR and 19f-NMR and mass spectrometric measurement, result is summed up as shown in table 4.
Table 4
Embodiment 3
Compound I e, its chemical structural formula is as follows:
The preparation method of formula Ie compound is as follows: 400mg Compound I c is added to DMF and dissolve, add 2.5eq. acetic acid, 2.5eq. paraformaldehyde, 2.5eq.NaBH 3cN, in room temperature reaction 15h, reacts complete, adds water, and ethyl acetate extraction, merges organic layer, and washing is dry, is spin-dried for, and rapid column chromatography obtains product, is Compound I e[285mg, productive rate: 69%].
Embodiment 4
Compound I g, its chemical structural formula is as follows:
The preparation method of Compound I g is as follows: 300mg Compound I f is added to DMF and dissolve, add 2.5eq. acetic acid, 2.5eq. paraformaldehyde, 2.5eq.NaBH 3cN, in room temperature reaction 15h, reacts complete, adds water, and ethyl acetate extraction, merges organic layer, and washing is dry, is spin-dried for, and rapid column chromatography obtains product [200mg, productive rate: 64%].
Embodiment 5
Compound I h, its chemical structural formula is as follows:
The preparation method of Compound I h is as follows: by 2.0eq. diacetyl oxide, 2.0eq. anhydrous formic acid mixes, stirring at room 0.5h, 100mg formula If compound is added to THF and dissolve, splash into reaction solution, in 0 ℃～room temperature reaction 1h, react complete, add water, ethyl acetate extraction, merge organic layer, washing, dry, be spin-dried for, rapid column chromatography obtains product, is compounds ib [90mg, productive rate: 84%].
Gained Compound I e, Compound I g and Compound I h thing have been carried out to hydrogen nuclear magnetic resonance 1h-NMR and 19f-NMR and mass spectrometric measurement, result is summed up as shown in table 6.
Table 6
drug effect and pharmacokinetics test
One, compound vitro inhibition mycobacterium tuberculosis active testing:
1, test method
Mycobacterium tuberculosis type strain H37Rv is from national DSMZ (ATCC27294), mycobacterium tuberculosis clinical separation strain B2[substance of medicines-resistant branched tubercle bacillus (MDRTB)] with the extensive Drug-Resistant Mycobacterium tuberculosis of B29[(XDRTB)] from the clinical separated preservation of Shanghai Pulmonary Hospital.Strain subject is proceeded to Middlebrook7H9 liquid nutrient medium, in 37 ℃, cultivate 2 weeks, draw to cultivate bacterium liquid a little, be placed in 4mL liquid nutrient medium, add 10～20 of diameter 2～3mm sterile glass beads, vibrate 20～30 seconds, quiescent setting 10～20 minutes, draw bacteria suspension supernatant, with liquid nutrient medium adjustment than turbid to 1 Maxwell unit, be equivalent to 1mg/mL standby.Target compound dissolves with DMSO, then is diluted to required experimental concentration with liquid nutrient medium.During detection, respectively get above-mentioned target compound solution 100 μ L and be added in 96 hole microwell plates, then add 10 -3the bacterium liquid 100 μ L of mg/mL concentration, make target compound concentration reach the final concentration of setting.37 ℃ of cultivations, the minimum inhibitory concentration of object observing compound to mycobacterium tuberculosis type strain H37Rv.
2, test-results
Table 7 has been summed up target compound mycobacterium tuberculosis type strain H37Rv has been suppressed to activity experiment result.Result display-object compound (Ib, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Im, In, Io, Ip, Iq, Is and Iu) has very strong restraining effect to H37Rv type strain.
Simultaneously, selection portion partial objectives for compound (Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Im, In, Io, Iq and Is) has been measured the restraining effect to substance of medicines-resistant branched tubercle bacillus (MDRTB) and extensive Drug-Resistant Mycobacterium tuberculosis (XDRTB), and test-results is summarised in table 8.Result shows that all target compounds have restraining effect very by force or to a certain degree to substance of medicines-resistant branched tubercle bacillus and extensive Drug-Resistant Mycobacterium tuberculosis.
Table 7
Target compound MIC(μg/mL)
Compounds ib 0.0625
Compound I c 0.125
Compound I d 0.03125
Compound I e 0.03125
Compound I f 0.0078
Compound I g 0.0078
Compound I h 0.03125
Compound I i 0.015
Compound I j 0.015
Compound I k 0.015
Compound I m 0.03125
Compound I n 0.03125
Compound I o 0.0078
Compound I p 0.0625
Compound I q 0.00195
Compound I r 0.25
Compound I s 0.03125
Compound I t 0.125
Compound I u 0.0625
Table 8
Target compound MIC(μg/mL)(MDRTB) MIC(μg/mL)(XDRTB)
Compound I d 0.125 0.03125
Compound I e 0.25 0.0625
Compound I f 0.0625 0.03125
Compound I g 0.0625 0.015
Compound I h 0.25 0.125
Compound I i 0.125 0.0625
Compound I j 0.0625 0.0625
Compound I k 0.0625 0.0625
Compound I m 0.0625 0.0625
Compound I n 0.125 0.125
Compound I o 0.03125 0.03125
Compound I q 0.0625 0.015
Compound I s 0.0078 0.0078
Two, pharmacokinetic experiment
1, experimental technique:
Laboratory animal: CD-1 mouse, male, 6～7 weeks; Body weight: 20～25g;
Trial-product preparation: by test compounds to be mixed with 0.2mg/mL(be intravenously administrable with) and 1.0mg/mL(be oral administration use), stand-by.Route of administration: oral/vein.Administration capacity and frequency: 5mL/kg, single-dose.
Sample collecting: gather blood according to following time point, 3 animals of each time point, get the about 0.5-1.0mL of whole blood.After administration, 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h get blood.All animals are all implemented euthanasia after completing test.
2, sample analysis and result
Sample analysis: use LC-MS/MS method to detect collected specimens.Using instrument model is SHIMADZU20A-API4000.
Pharmacokinetic data is analyzed: use WinNolin, according to non-compartment model method, gained Plasma Concentration data are carried out to matching and calculating, partial results is summarised in table 9.
The part target compound pharmacokinetic parameter that table 9 calculates according to non-compartment model method
Test-results in CD-1 mouse shows that the compounds of this invention has good pharmacokinetic characteristic, comprises that clearance rate is low, oral absorption good and the attribute such as long half time.
Above embodiment is only representational.Visible by above-described embodiment, compound of the present invention has very strong activity to mycobacterium tuberculosis, and first pass effect is less, and effectively bioavailability is high, has using dosage few, the advantage that side effect is little when treatment tuberculosis and relevant indication.Compound of the present invention can also combine and make oral preparations (tablet or capsule etc.) with dissimilar pharmaceutical salts.The tablet made from the compounds of this invention or capsule can be taken once a day or repeatedly.The compounds of this invention also can be with other its medicines in conjunction with making compound preparation, or (include but not limited to following medicine: vazadrine with other drug, Rifampin, pyrazinoic acid amide, Tibutol, Moxifloxacin, Bedaquiline, PA-824, rifapentine, rifabutin, Streptomycin sulphate, kantlex, amikacin, Gatifloxacin, levofloxacin, Ofloxacine USP 23, Ciprofloxacin, capromycin, ethionamide, seromycin, para-aminosalicylic acid, Thioacetazone, clarithromycin, clofazimine, amoxicillin-clavulanic acid, imipenum, meropenem, Viothenate, terizidone, clofazimine, Delamanid, AZD5847, Sutezolid, and SQ-109) drug combination clinically.
Above-described embodiment is only explanation technical conceive of the present invention and feature, and its object is to allow person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.

Claims (12)

1. the nitroimidazole heterocyclic compound with general formula (I), its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form
Wherein:
R 1represent H, CH 2f, CHF 2, CF 3, C nh 2n+1, C nh 2n-1, NO 2, F, Cl, Br, I, CN, OH, OC nh 2n+1, OC nh 2n-1, SH, SC nh 2n+1, SC nh 2n-1, NH 2, NHC nh 2n+1, NHC nh 2n-1, N (C nh 2n+1) (C nh 2n+1), N (C nh 2n+1) (C nh 2n-1), N (C nh 2n-1) (C nh 2n-1), NH (COC nh 2n+1) or NH (COC nh 2n-1);
R 2represent H, CH 2f, CHF 2, CF 3, C nh 2n+1or C nh 2n-1;
R 3represent H, C nh 2n+1, C nh 2n-1, CHO, COC nh 2n+1, COC nh 2n-1, COOC nh 2n+1, COOC nh 2n-1, NCONH 2, CONH (C nh 2n+1) or CONH (C nh 2n-1);
R 4represent CH 2f, CHF 2or CF 3;
A represents O, S, NH, NC nh 2n+1, NC nh 2n-1, NCOC nh 2n+1, NCOC nh 2n-1, NCOOC nh 2n+1, NCOOC nh 2n-1, NCONH 2, NCONH (C nh 2n+1) or NCONH (C nh 2n-1);
B and E represent C independently mh 2m-4, C nh 2n, C qh 2q-2or C ph 2p-8;
D is C mh 2m-4, C nh 2n, C qh 2q-2, C ph 2p-8, C mh 2m-4c 6h 4o, C nh 2nc 6h 4o, C qh 2q-2c 6h 4o, C ph 2p-8c 6h 4o, C mh 2m-4c 5h 3nO, C nh 2nc 5h 3nO, C qh 2q-2c 5h 3nO, C ph 2p-8c 5h 3nO, C mh 2m-4c 4h 2n 2o, C nh 2nc 4h 2n 2o, C qh 2q-2c 4h 2n 2or C ph 2p-8c 4h 2n 2o;
W, M, Y and Z represent C-H, N, C-C independently nh 2n+1, C-C nh 2n, C-C nh 2n-1, C-OH, C-OC nh 2n+1, C-OC nh 2n-1, C-OC nh 2n, C-C 6h 5, C-C nh 2nc 6h 5, C-OC 6h 5, C-OC nh 2nc 6h 5, C-C 5h 4n, C-C nh 2nc 5h 4n, C-OC 5h 4n, C-OC nh 2nc 5h 4n, C-C 4h 3n 2, C-C nh 2nc 4h 3n 2, C-OC 4h 3n 2, C-OC nh 2nc 4h 3n 2, C-CN, C-NO 2, C-CH 2f, C-CHF 2, C-CF 3, C-OCH 2f, C-OCHF 2, C-OCF 3, C-F, C-Cl, C-Br or C-I;
Above-mentioned n is greater than zero integer; M is more than or equal to 3 integer; P is more than or equal to 7 integer; Q is more than or equal to 3 integer;
In formula (I), when W, M, Y and Z are all not N, R 4for CH 2f or CHF 2; Described nitroimidazole heterocyclic compound, in the meta-bolites of its pharmacologically acceptable salt, hydrate, prodrug and metabolism formation in any form, the hydrogen of commutativity can be replaced by deuterium.
2. nitroimidazole heterocyclic compound according to claim 1, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form, is characterized in that: in formula I, A is O or S, R 1, R 2,r 3, R 4, B, C, D, W, M, Y and Z definition with claim 1.
3. nitroimidazole heterocyclic compound according to claim 1, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form, is characterized in that: in formula I, A is O or S, and E is C nh 2n, R 1for H, R 2, R 3, R 4, B, D, W, M, Y and Z definition with claim 1.
4. nitroimidazole heterocyclic compound according to claim 3, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form, is characterized in that: in formula I, A is O, and E is CH 2, R 1for H, R 2for H, now its structure is as shown in the formula (II):
In formula II, R 3, R 4, B, D, W, M, Y and Z definition with claim 1;
In formula II, when W, M, Y and Z are all not N, R 4for CH 2f or CHF 2.
5. nitroimidazole heterocyclic compound according to claim 4, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form, is characterized in that: in formula (II), W and Y are CH, now its structure is as shown in the formula (III):
In formula III, R 3, R 4, B, M and Z definition with claim 1;
In formula III, when M and Z are all not N, R 4for CH 2f or CHF 2.
6. nitroimidazole heterocyclic compound according to claim 5, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form, is characterized in that: in formula (III), B is CH 2, CH (CH 3), CH (CH 2cH 3), CH (CH 2cH 2cH 3) or CHCH (CH 3) 2.
7. according to the nitroimidazole heterocyclic compound described in claim 5 or 6, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form, is characterized in that: in formula (III), and R 3represent H, CH 3, CH 2cH 3, CH 2cH 2cH 3, CHO, COC nh 2n+1, wherein n is the integer between 1～6.
8. according to the nitroimidazole heterocyclic compound described in claim 5 or 6, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that metabolism forms in any form, is characterized in that: in formula (III), D is CH 2, CH (CH 3), CH (CH 2cH 3), CH (CH 2cH 2cH 3), CHCH (CH 3) 2or CH 2c 6h 4.
9. nitroimidazole heterocyclic compound according to claim 5, its pharmacologically acceptable salt, hydrate, the meta-bolites that prodrug or in any form metabolism form, is characterized in that: described compound is a kind of of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It) and formula (Iu) expression:
10. the nitroimidazole heterocyclic compound described in any one claim in claim 1 to 9, its pharmacologically acceptable salt, hydrate, the purposes of the meta-bolites that prodrug or in any form metabolism form in the medicine of the preparation treatment indication relevant with cell walls mycolic acid complex functionality with mycobacterium tuberculosis protein matter.
11. purposes according to claim 10, is characterized in that: the described indication relevant with cell walls mycolic acid complex functionality to mycobacterium tuberculosis protein matter is tuberculosis.
12. 1 kinds of pharmaceutical compositions that are used for the treatment of the indication relevant with cell walls mycolic acid complex functionality with mycobacterium tuberculosis protein matter, it is characterized in that: the effective constituent of described pharmaceutical composition at least comprises the nitroimidazole heterocyclic compound described in any one claim in claim 1 to 9, its pharmacologically acceptable salt, hydrate, the meta-bolites that prodrug or in any form metabolism form.
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