CN106543106B - N- benzyl benzamide compounds and preparation method thereof - Google Patents
N- benzyl benzamide compounds and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/38—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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Abstract
The present invention relates to N- benzyl benzamide compounds, preparation method and medical usage shown in formula (I) and using it as the antitubercular pharmaceutical composition of active ingredient.More particularly, it relates to N- benzyl benzamide compounds, benzyl contraposition on substituent group be nitrogen heterocyclic ring segment, wherein R represents trifluoromethyl, nitro in formula (I)；X represents 4- thio-morpholinyls, octahydro -2H- iso-indoles -2- bases, isoindoline -2- bases, 4- substituted piperidine -1- bases, (4- substituted-phenyls) piperidin-1-yl, (4- substituted-phenyls) piperazine -1- bases.
Description
Technical field
The invention belongs to medicinal chemistry arts, be related to the N- benzyls benzamide compound with anti-tubercular and its
Preparation method, and the antitubercular pharmaceutical composition containing them；It is more particularly related to a kind of N- benzyls -3-
Nitro -5- trifluoromethyl benzamides and N- benzyl -3,5- dinitrobenzamide class compounds, the substitution that benzyl aligns
Base is 4- thio-morpholinyls, octahydro -2H- iso-indoles -2- bases, isoindoline -2- bases, 4- substituted piperidine -1- bases, (4- substituted benzenes
Base) piperidin-1-yl, (4- substituted-phenyls) piperazine -1- bases.
Background technology
Tuberculosis (TB) be by seriously endanger caused by mycobacterium tuberculosis (MTB) serious infectious diseases of human health it
One.Since the 1980s, drug resistance TB, the incidence of especially multi-drug resistant TB (MDR-TB) constantly rise and TB with
HIV/AIDS, which is combined, makes TB epidemic situations rise once again, becomes the great public health problem and social concern of global concern.According to system
Meter, the whole world have 8,000,000 newly-increased TB patients, nearly 3,000,000 people to die of tuberculosis every year, and nearly 1/3 population carries latent form tubercle bacillus, tool
There is potential initiation potential.Traditional anti-TB drugs, such as streptomysin, isoniazid, rifampin, ethambutol and pyrazinamide connection
Sharing medicine can make 85% or more first control lunger's recovery from illness, but there are treatment cycle length (be more than 6 months) and to MDR-TB
Invalid disadvantage, at the same it is not strong to the effect of latent form MTB, therefore anti-TB new drugs are researched and developed, realize effective treatment and control to TB
Make extremely urgent (external medicine-antibiotic fascicle 2009,30 (1)：19-24).
Fortunately, quinoline (ATP is reached as the 1st in the past 40 years anti-TB new drugs shellfish with completely new mechanism of action
Synthetase inhibitors) treatment MDR-TB was approved by the fda in the United States in 2012.It is inspired by this, multiple big systems global in recent years
Medicine company and research unit increase the R&D intensity of Antituberculous new drug, and it is several with different role mechanism to disclose report
Treating tuberculosis candidate compound.These candidate compounds are at present or in clinical experimental stage or in the preclinical study stage.
2011, Switzerland scientist Ma Kaluowa etc. disclosed the 4H- benzos that a kind of 2- bit substituents are piperazine -1- bases
The synthesis of [e] [1,3] thiazine -4- ketone compounds and anti-tubercular (CN 201180055813.5).It represents object
PBTZ169 have outstanding inside and outside wide spectrum anti-tubercular (EMBO Mol Med, 2014,6：372–383).PBTZ169 in
Enter I phase clinical researches in Russia within 2016.
Present inventor has performed extensive researchs, by 4H- benzos [e] [1,3] thiophene of the parent nucleus piperazine -1- bases of PBTZ169
Piperazine -4- ketone open loops, design have synthesized N- benzyl -3- nitro -5- trifluoromethyl benzamides and N- benzyl -3,5- dinitrobenzene first
Amides compound, and determine their anti-tubercular.It finally found that, in the benzyl contraposition of document report different from the past
Substituent group be 4- thio-morpholinyls, octahydro -2H- iso-indoles -2- bases, isoindoline -2- bases, 4- substituted piperidine -1- bases, (4-
Substituted-phenyl) piperidin-1-yl, (4- substituted-phenyls) piperazine -1- bases compound have unexpected strong anti-tubercular, with
PBTZ169 and a line anti-tubercular drug isoniazid are compared with rifampin, have more superior anti-tubercular.
Invention content
The N- benzyl benzamide compounds that the object of the present invention is to provide one kind to be indicated by leading to formula (I),
Wherein：
R represents CF3、NO2；
X is selected from following nitrogen heterocyclic ring segment：
Y represents F, Cl, CF3、OCF3、OCH3；Z represents CH, N.
The present invention specifically includes following compound：
3- nitro -5- trifluoromethyls-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [(4- thio-morpholinyls) benzyl] benzamide；
3,5- dinitro-N- [4- (octahydro -2H- iso-indoles -2- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (isoindoline -2- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- fluorine resources -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- Chloperastine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- trifluoromethoxies piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- methoxy piperide -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- chlorphenyls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- trifluoromethyls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperazine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- chlorphenyls) piperazine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- trifluoromethyls) piperazine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperazine -1- bases) benzyl] benzamide.
Preferably, N- benzyls benzamide compound is selected from：
3- nitro -5- trifluoromethyls-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [(4- thio-morpholinyls) benzyl] benzamide；
3,5- dinitro-N- [4- (octahydro -2H- iso-indoles -2- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperazine -1- bases) benzyl] benzamide.
The invention further relates to the preparation methods of formula (I) compound, as shown in reaction scheme 1.
Reaction route 1：
By formula (II) compound and formula (III) compound, in the presence of nonpolar solvent and bis- (the 2- oxygen of condensing agent are added
Generation -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride (BOP-Cl), meet needs with excessive formula (III) compound, at -5 DEG C~40 DEG C,
With or without being stirred to react under pressure condition 2.5~30 hours, formula (I) compound is obtained,
In reaction route 1, R and X are defined as the aforementioned.
Condensing agent is added in nonpolar solvent, make formula (II) compound and formula (III) compound by condensation reaction come
Prepare formula (I) compound.
Nonpolar solvent for this reaction is selected from dichloromethane, chloroform, tetrahydrofuran, dioxane or hexamethylene, institute
The condensing agent stated is selected from bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides (BOP-Cl).
Formula (II) compound for being used as starting material in the present invention is known compound, and there is supply of commodities in the country.Formula (III)
Compound is also known compound, and is easily implemented with reference to known method in existing publication, such as Pethe K etc.,
Nat.Med.2013,19,1157-1160；Kang S etc., J.Med.Chem.2014,57,5293-5305.
The present invention also provides contain treating tuberculosis composition of formula as defined above (I) compound as active constituent.Medicine
The weight ratio of the compounds of this invention that compositions contain in the composition is 0.1~99.9%, and pharmaceutically acceptable carrier exists
Weight ratio in composition is 0.1~99.9%.Pharmaceutical composition is to be suitble to medicinal dosage form to exist.The drug of the present invention
Composition can be prepared into any pharmaceutical dosage form.Preferably, medicinal preparation be tablet, sugar coated tablet, film coated tablet,
Enteric coated tablet, sustained-release tablet, capsule, hard capsule, soft capsule, Duracaps, powder.
The pharmaceutical composition of the present invention, as dosage form, the effective quantity of the compounds of this invention contained in every dose is 0.1
~1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, also can refer to each taking agent
Amount, such as each taking 100mg.
The pharmaceutical composition of the present invention is in the solid for being prepared into pulvis, tablet, dispersible pulvis, capsule, cachet form
When pharmaceutical preparation, solid carrier can be used.Workable solid carrier is preferably selected from diluent, flavoring agent, solubilizer, lubrication
One or more substances in agent, suspending agent, adhesive, swelling agent etc., or can be encapsulating substance.Suitable solid carrier includes
Magnesium carbonate, magnesium stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, carboxymethyl cellulose
Sodium, cocoa butter etc..Since they are easy to be administered, tablet, pulvis, cachet and capsule etc. represent best oral administration solid system
Agent.
It is uniform for ease of administration and dosage, said medicine preparation is configured to dosage unit form and is particularly advantageous.
The dosage unit form of preparation refers to the physical separation unit for being suitable for single dose, and each unit, which contains, generates desired control
The active constituent for the predetermined amount of therapeutic effect calculated.This dosage unit form can be packaged form, such as tablet, capsule or dress
Pulvis in tubule or bottle.
Although the amount of contained active constituent can change in dosage unit form, generally according to selected active constituent
Effect is adjusted within the scope of 1~800mg.
When formula (I) reactive compound of the present invention is used as the drug for the treatment of mycobacterium tuberculosis infection, preferably first
Stage gives the amount of 6~14mg/kg weight.But dosage can be with sick human needs, the seriousness of the infection to be treated, institute
It selects compound etc. and changes.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Generally, start treatment
Amount is then gradually increased dosage, until reaching optimum therapeuticing effect less than the optimal dose of active constituent.It rises for convenience
See, total daily dose can be divided into several parts, score time administration.
The present invention also provides compounds shown in formula (I) or the pharmaceutical composition containing the compound to prepare treatment tuberculosis
Drug in application.
Tuberculosis of the present invention includes active tuberculosis, single resistant tuberculosis, more resistant tuberculosis and resistance to extensively
Multiple medicine tuberculosis.
Tuberculosis of the present invention includes pulmonary tuberculosis, the outer tuberculosis of lung.
As described above, the compounds of this invention is equivalent to the activity of mycobacterium tuberculosis or is better than control compound
PBTZ169 and a line anti-tubercular drug isoniazid and rifampin.For example, embodiment 2,3,7 and 14 compounds are to tuberculosis branch bar
The external activity of bacterium type strain H37Rv ATCC 27294 is compound PBTZ169, isoniazid and rifampin >=2 times, to facing
The external activity of bed separation strains MDR-MTB 20161 (to rifampin and Isoniazid-resistant) is the 2 of compound PBTZ169->7 times.
The compound of the present invention is for existing product, the better efficacy in terms for the treatment of tuberculosis, active higher, side effect
Lower, stability is good, and synthesis technology is simpler, and cost is substantially reduced, and is suitble to large-scale production, the present invention that drug is prepared
Also have the characteristics that high income and purity are high.
Specific implementation mode
In the examples below, the present invention will be more specifically explained.It should be understood that the following example is intended to illustrate hair
It is bright without to the scope of the present invention constitute any restrictions.
1 3- nitro -5- trifluoromethyls-N- of embodiment [4- (4- trifluoromethyl piperidine -1- bases) benzyl] benzamide
Under nitrogen protection, by 3- nitros -5- (trifluoromethyl) benzoic acid (0.23g, 0.1mmol), 4- (4- (trifluoromethyl)
Piperidin-1-yl) aniline, bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride (BOP-Cl, 0.28g, 0.11mmol), triethylamine
The mixture of (0.15g, 0.15mmol) and dichloromethane (25ml) is stirred to react 2h at room temperature.Reaction terminates, washing
(25ml), then organic layer is washed with saturated nacl aqueous solution.Concentration, residue obtain off-white powder through column chromatography for separation
0.33g (yield 70.0%), mp:143-144℃.
1H NMR(500MHz,CDCl3) δ 9.54 (t, J=5.5Hz, 1H), 8.97 (s, 1H), 8.66 (d, J=9.0Hz,
2H), 7.21 (d, J=8.5Hz, 2H), 6.93 (d, J=8.5Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.75 (d, J=
12.5Hz, 2H), 2.66-2.71 (m, 2H), 2.45-2.49 (m, 1H), 1.85 (d, J=12.5Hz, 2H), 1.49-1.57 (m,
2H)。
MS-ESI(m/z):476.4(M+H)+。
HRMS-ESI:m/z Calcd.for C21H20F6N3O3(M+H)+:476.38531；Found476.38303.
Embodiment 23,5- dinitros-N- [(4- thio-morpholinyls) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (thiomorpholine -4- bases) aniline reaction
Obtain off-white powder (yield 62.0%), mp:184-186℃.
1H NMR(500MHz,CDCl3) δ 9.65 (t, J=5.5Hz, 1H), 9.08 (d, J=2.0Hz, 2H), 8.95 (s, J
=2.0Hz, 1H), 7.21 (d, J=9.0Hz, 2H), 6.89 (d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.47-
3.50(m,4H),2.63-2.65(m,4H)。
MS-ESI(m/z):403.2(M+H)+。
HRMS-ESI:m/z Calcd.for C18H19O5N4S(M+H)+:403.19172；Found 403.19065.
Embodiment 33,5- dinitros-N- [4- (octahydro -2H- iso-indoles -2- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (octahydro -2H- iso-indoles -2- bases) benzene
Amine reacts to obtain off-white powder (yield 67.1%), mp:188-189℃.
1H NMR(500MHz,CDCl3) δ 9.65 (t, J=5.5Hz, 1H), 9.08 (d, J=2.0Hz, 2H), 8.95 (s, J
=2.0Hz, 1H), 7.21 (d, J=9.0Hz, 2H), 6.89 (d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 2.97-
2.99(m,4H),1.58-1.53(m,6H),1.38-1.36(m,4H)。
MS-ESI(m/z):425.4(M+H)+。
HRMS-ESI:m/z Calcd.for C22H25O5N4(M+H)+:424.39263；Found 425.39195.
Embodiment 43,5- dinitros-N- [4- (isoindoline -2- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (isoindoline -2- bases) aniline reaction
Obtain off-white powder (yield 75.2%).
1H NMR(500MHz,CDCl3) δ 9.65 (t, J=5.5Hz, 1H), 9.08 (d, J=2.0Hz, 2H), 8.95 (s, J
=2.0Hz, 1H), 7.46-7.49 (m, 4H), 7.26 (d, J=9.0Hz, 2H), 6.78 (d, J=9.0Hz, 2H), 4.67-4.69
(m, 2H), 4.44 (d, J=5.5Hz, 2H).
MS-ESI(m/z):419.1(M+H)+。
HRMS-ESI:m/z Calcd.for C22H19O5N4(M+H)+:419.09155；Found 419.09063.
Embodiment 53,5- dinitros-N- [4- (4- fluorine resources -1- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid is obtained with 4- (fluorine resources -1- bases) aniline reaction
Off-white powder (yield 72.1%).
1H NMR(500MHz,CDCl3) δ 9.64 (t, J=5.5Hz, 1H), 9.09 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.21 (d, J=9.0Hz, 2H), 6.91 (d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.75
(d, J=12.5Hz, 2H), 2.67-2.71 (m, 2H), 2.45-2.49 (m, 1H), 1.85 (d, J=12.5Hz, 2H), 1.48-
1.59(m,2H)。
MS-ESI(m/z):403.1(M+H)+。
HRMS-ESI:m/z Calcd.for C19H20FO5N4(M+H)+:403.09102；Found 403.09033.
Embodiment 63,5- dinitros-N- [4- (4- Chloperastine -1- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid is obtained with 4- (Chloperastine -1- bases) aniline reaction
Off-white powder (yield 71.8%).
1H NMR(500MHz,CDCl3) δ 9.65 (t, J=5.5Hz, 1H), 9.09 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.20 (d, J=9.0Hz, 2H), 6.90 (d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.75
(d, J=12.5Hz, 2H), 2.66-2.70 (m, 2H), 2.45-2.49 (m, 1H), 1.84 (d, J=12.5Hz, 2H), 1.49-
1.57(m,2H)。
MS-ESI(m/z):419.8(M+H)+。
HRMS-ESI:m/z Calcd.for C19H20FO5N4(M+H)+:419.79112；Found 419.79015.
Embodiment 73,5- dinitros-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- trifluoromethyl piperidine -1- bases) benzene
Amine reacts to obtain off-white powder (yield 57.5%), mp:149-151℃.
1H NMR(500MHz,CDCl3) δ 9.65 (t, J=5.5Hz, 1H), 9.09 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.21 (d, J=9.0Hz, 2H), 6.93 (d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.75
(d, J=12.5Hz, 2H), 2.66-2.71 (m, 2H), 2.45-2.49 (m, 1H), 1.85 (d, J=12.5Hz, 2H), 1.48-
1.57(m,2H)。
MS-ESI(m/z):453.2(M+H)+。
HRMS-ESI:m/z Calcd.for C20H20F3O5N4(M+H)+:453.19592；Found 453.19602.
Embodiment 83,5- dinitros-N- [4- (4- trifluoromethoxies piperidin-1-yl) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- trifluoromethoxies piperidin-1-yl)
Aniline reaction obtains off-white powder (yield 68.4%).
1H NMR(500MHz,CDCl3) δ 9.64 (t, J=5.5Hz, 1H), 9.09 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.20 (d, J=9.0Hz, 2H), 6.88 (d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.74
(d, J=12.5Hz, 2H), 2.66-2.71 (m, 2H), 2.45-2.49 (m, 1H), 1.86 (d, J=12.5Hz, 2H), 1.48-
1.58(m,2H)。
MS-ESI(m/z):469.4(M+H)+。
HRMS-ESI:m/z Calcd.for C20H20F3O6N4(M+H)+:469.37373；Found 469.37365.
Embodiment 93,5- dinitros-N- [4- (4- methoxy piperide -1- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- methoxy piperide -1- bases) aniline
React to obtain off-white powder (yield 70.0%).
1H NMR(500MHz,CDCl3) δ 9.64 (t, J=5.5Hz, 1H), 9.08 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.20 (d, J=9.0Hz, 2H), 6.91 (d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.75
(d, J=12.5Hz, 2H), 3.22 (s, 3H), 2.66-2.71 (m, 2H), 2.43-2.46 (m, 1H), 1.85 (d, J=12.5Hz,
2H),1.45-1.53(m,2H)。
MS-ESI(m/z):415.4(M+H)+。
HRMS-ESI:m/z Calcd.for C20H23O6N4(M+H)+:415.37044；Found 415.37078.
Embodiment 10 3,5- dinitros-N- [4- (4- (4- fluorophenyls) piperidin-1-yl) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- fluorophenyls) piperidin-1-yl) benzene
Amine reacts to obtain off-white powder (yield 75.3%).
1H NMR(500MHz,CDCl3) δ 9.56 (t, J=5.5Hz, 1H), 8.89 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.97 (d, J=9.0Hz, 2H), 7.18 (d, J=9.0Hz, 2H), 6.87 (d, J=9.0Hz, 2H), 6.79
(d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.74 (d, J=12.5Hz, 2H), 2.67-2.73 (m, 2H),
2.55-2.59 (m, 1H), 1.86 (d, J=12.5Hz, 2H), 1.66-1.69 (m, 2H).
MS-ESI(m/z):479.6(M+H)+。
HRMS-ESI:m/z Calcd.for C25H24FO5N4(M+H)+:479.57411；Found 479.57379.
Embodiment 11 3,5- dinitros-N- [4- (4- (4- chlorphenyls) piperidin-1-yl) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- chlorphenyls) piperidin-1-yl) benzene
Amine reacts to obtain off-white powder (yield 66.8%).
1H NMR(500MHz,CDCl3) δ 9.56 (t, J=5.5Hz, 1H), 8.89 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.97 (d, J=9.0Hz, 2H), 7.18 (d, J=9.0Hz, 2H), 6.87 (d, J=9.0Hz, 2H), 6.79
(d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.74 (d, J=12.5Hz, 2H), 2.67-2.73 (m, 2H),
2.55-2.59 (m, 1H), 1.88 (d, J=12.5Hz, 2H), 1.66-1.68 (m, 2H).
MS-ESI(m/z):495.1(M+H)+。
HRMS-ESI:m/z Calcd.for C25H24ClO5N4(M+H)+:495.07011；Found 495.07079.
Embodiment 12 3,5- dinitros-N- [4- (4- (4- trifluoromethyls) piperidin-1-yl) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- trifluoromethyls) piperidines -1-
Base) aniline reaction obtains off-white powder (yield 71.9%).
1H NMR(500MHz,CDCl3) δ 9.56 (t, J=5.5Hz, 1H), 8.89 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.97 (d, J=9.0Hz, 2H), 7.18 (d, J=9.0Hz, 2H), 6.87 (d, J=9.0Hz, 2H), 6.79
(d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.76 (d, J=12.5Hz, 2H), 2.67-2.73 (m, 2H),
2.55-2.58 (m, 1H), 1.89 (d, J=12.5Hz, 2H), 1.68-1.71 (m, 2H).
MS-ESI(m/z):529.3(M+H)+。
HRMS-ESI:m/z Calcd.for C26H24F3O5N4(M+H)+:529.30034；Found 529.30019.
Embodiment 13 3,5- dinitros-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperidin-1-yl) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- Trifluoromethoxyphen-ls) piperidines-
1- yls) aniline reaction obtains off-white powder (yield 75.4%), mp:210-211℃.
1H NMR(500MHz,CDCl3) δ 9.56 (t, J=5.5Hz, 1H), 8.89 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 7.97 (d, J=9.0Hz, 2H), 7.18 (d, J=9.0Hz, 2H), 6.87 (d, J=9.0Hz, 2H), 6.79
(d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.76 (d, J=12.5Hz, 2H), 2.67-2.73 (m, 2H),
2.55-2.57 (m, 1H), 1.89 (d, J=12.5Hz, 2H), 1.68-1.70 (m, 2H).
MS-ESI(m/z):545.3(M+H)+。
HRMS-ESI:m/z Calcd.for C26H24F3O6N4(M+H)+:545.28034；Found 545.28001.
Embodiment 14 3,5- dinitros-N- [4- (4- (4- fluorophenyls) piperazine -1- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- fluorophenyls) piperazine -1- bases) benzene
Amine reacts to obtain off-white powder (yield 83.5%), mp:225-227℃.
1H NMR(500MHz,CDCl3) δ 9.56 (t, J=5.5Hz, 1H), 8.89 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 8.17 (d, J=9.0Hz, 2H), 7.24 (d, J=9.0Hz, 2H), 6.97 (d, J=9.0Hz, 2H), 6.89
(d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.46-3.48 (m, 4H), 3.21-3.24 (m, 4H).
MS-ESI(m/z):480.3(M+H)+。
HRMS-ESI:m/z Calcd.for C24H22FO5N5(M+H)+:480.28324；Found 480.28351.
Embodiment 15 3,5- dinitros-N- [4- (4- (4- chlorphenyls) piperazine -1- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- chlorphenyls) piperazine -1- bases) benzene
Amine reacts to obtain off-white powder (yield 78.8%).
1H NMR(500MHz,CDCl3) δ 9.56 (t, J=5.5Hz, 1H), 8.89 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 8.17 (d, J=9.0Hz, 2H), 7.23 (d, J=9.0Hz, 2H), 6.97 (d, J=9.0Hz, 2H), 6.88
(d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.46-3.48 (m, 4H), 3.21-3.24 (m, 4H).
MS-ESI(m/z):496.5(M+H)+。
HRMS-ESI:m/z Calcd.for C24H23ClO5N5(M+H)+:496.48124；Found496.48091.
Embodiment 16 3,5- dinitros-N- [4- (4- (4- trifluoromethyls) piperazine -1- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- trifluoromethyls) piperazine -1-
Base) aniline reaction obtains off-white powder (yield 78.8%).
1H NMR(500MHz,CDCl3) δ 9.56 (t, J=5.5Hz, 1H), 8.89 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 8.21 (d, J=9.0Hz, 2H), 7.24 (d, J=9.0Hz, 2H), 6.97 (d, J=9.0Hz, 2H), 6.86
(d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.46-3.47 (m, 4H), 3.21-3.23 (m, 4H).
MS-ESI(m/z):530.2(M+H)+。
HRMS-ESI:m/z Calcd.for C25H23F3O5N5(M+H)+:530.18624；Found 530.18588.
Embodiment 17 3,5- dinitros-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperazine -1- bases) benzyl] benzamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- Trifluoromethoxyphen-ls) piperazine-
1- yls) aniline reaction obtains off-white powder (yield 66.1%).
1H NMR(500MHz,CDCl3) δ 9.56 (t, J=5.5Hz, 1H), 8.89 (d, J=2.0Hz, 2H), 8.95 (t, J
=2.0Hz, 1H), 8.18 (d, J=9.0Hz, 2H), 7.24 (d, J=9.0Hz, 2H), 6.97 (d, J=9.0Hz, 2H), 6.88
(d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.46-3.48 (m, 4H), 3.21-3.23 (m, 4H).
MS-ESI(m/z):546.3(M+H)+。
HRMS-ESI:m/z Calcd.for C25H23F3O6N5(M+H)+:546.28604；Found 546.28564.
Biological Examples 1
External anti-mycobacteria activity test
The anti-tubercular of the compounds of this invention is by measuring it to mycobacterium tuberculosis type strain MTBH37Rv ATCC
The minimal inhibitory concentration (MIC, μ g/mL) of 27294 and clinical separation strain MDR-MTB 20161 (to rifampin and Isoniazid-resistant)
Come what is indicated.In this experiment, it is compared with candidate compound PBTZ169 and a line anti-tubercular drug isoniazid and rifampin
Medicine.Minimal inhibitory concentration measures as follows：Sterile 48 orifice plate (the special microtest plate of tulase quick medicine-sensitive), by susceptibility
Experimental design requirement, each hole are separately added into 2 times of concentration cultures (improvement Michaelis 7H9 fluid nutrient mediums) diluted drug.Respectively
The first solution of debita spissitudo is made in compound, and two times of concentration of each compound used therefor are diluted to culture medium (2 ×), each change
Each 10 gradients of object are closed, 48 orifice plates are added per 100 μ L of hole, the final concentration of investigational agent is respectively 8,4,2 ... 0.015 μ g/mL.Mark
Quasi- strain H37Rv ATCC 27294 and clinical separation strain MDR-MTB20161 are inoculated with 100 μ l per hole, are 4 × 10 per hole bacterium amount- 3mg.Every plate is all provided with the growth Positive control wells that 2 are free of antimicrobial and two right with the growth feminine gender of distilled water substitutive medium
According to hole, surrounding is sealed with adhesive tape after 48 orifice plates are capped, and is placed in 37 DEG C of incubations of wet box.Growth positive pair is observed after 3rd day
According to hole and negative growth control wells, when observing that the two has clear difference, to the quantity and form of each test hole bacterial growth
It is observed, judgement inhibition or drug resistance and record are once confirmed as a result, being observed and recorded again after the 7th day.Pair of asepsis growth
Concentration according to contained drug minimum in hole is minimal inhibitory concentration (MIC).Measurement result is listed in table 1.
The external activity of 12 plants of mycobacterium tuberculosis of section Example compound pair of table
MTBa:MTB H37Rv ATCC 27294
MDR-MTBb：MDR-MTB 20161 (to rifampin and Isoniazid-resistant)
The external activity of part of compounds of the present invention is only enumerated in above-mentioned table, other compound structures of the invention are similar,
It is numerous to list herein with the external activity effect same or similar with above compound.
Biological Examples 1
Oral Acute Toxicity is tested
To measure the Oral Acute Toxicity of the compounds of this invention, 1 compound of embodiment and 2 compound of embodiment are carried out
The solution of the two compounds containing various concentration is taken orally and awards male mice, dosage 0.1ml/10g by acute toxicity testing
Weight, count dead mouse amount respectively after 7 days, and the median lethal dose (LD of each compound is calculated with Bliss programs50).As a result it is listed in table 2
In.
The Mouse oral acute toxicity of 2 Examples 1 and 2 compound of table
The experimental results showed that these toxicity of compound are very low, it is very suitable for medicinal.
Composition embodiment
1 coating tablet of embodiment
Core formulation：
Mentioned component is taken to be uniformly mixed, 100 labels are made in whole grain of being sieved after granulation, dry, tabletting.Coating fluid prescription：
Opadry (Opadry) 5g, the coating of 80% appropriate amount of ethanol.
2 capsule of embodiment
Prescription：
Preparation method：
Recipe quantity supplementary material is taken, is sieved respectively, 5% polyvinylpyrrolidone alcohol liquid and Tween 80 softwood is added, with 20
Mesh sieve granulation, dries at 15 DEG C of room temperature, lauryl sodium sulfate is added, be uniformly mixed, and No. 0 glue soluble in the stomach is packed by 0.27g/S
Capsule, sample examination, dissolution limit are Q=80%, and content should be the 90~110% of labelled amount.
3 granule of embodiment
The compound 100g of Example 3, is added appropriate dextrin, Steviosin, dry granulation, whole grain, packing to get.
7 injection of embodiment
The compound 150g of Example 7 is dissolved in water, and another sodium chloride, ethyl-para-hydroxybenzoate heat water dissolution, mix
It is even, adjust pH value 5-7.Water for injection is diluted to 1000ml, is filtered with hollow-fibre membrane, filling, sterilizing to get.
10 freeze-dried powder of embodiment
The compound 150g of Example 10 is dissolved in water, and separately plus mannitol 500g heats water dissolution, mixing, water for injection
It is diluted to 5000ml, is filtered with hollow-fibre membrane, filling, sterilizing is lyophilized up to freeze-dried powder.
14 dripping pill of embodiment
The compound 20g of Example 14 is spare as bulk pharmaceutical chemicals；Dripping pill matrix 200g is weighed, 80 DEG C of thawings are heated to,
It stirs evenly；It adds raw materials into excipient matrix while stirring, stirring 30min is allowed to uniform, and fluid temperature is kept to be not less than 60
℃；Prepared liquid is injected in pill dripping machine, is dripped into dripping pill, you can.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. compound shown in formula (I),
Wherein：
R represents CF3、NO2；
X is selected from following nitrogen heterocyclic ring segment：
Wherein, Y represents F, Cl, Br, CF3、OCF3、OCH3；Z represents CH, N.
2. compound shown in formula (I) according to claim 1, which is characterized in that its compound is：3- nitro -5- trifluoros
Methyl-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [(4- thio-morpholinyls) benzyl] benzamide；
3,5- dinitro-N- [4- (octahydro -2H- iso-indoles -2- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (isoindoline -2- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- fluorine resources -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- Chloperastine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- trifluoromethoxies piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- methoxy piperide -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- chlorphenyls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- trifluoromethyls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperidin-1-yl) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperazine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- chlorphenyls) piperazine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- trifluoromethyls) piperazine -1- bases) benzyl] benzamide；
3,5- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperazine -1- bases) benzyl] benzamide.
3. a kind of method preparing formula described in claims 1 or 2 (I) compound, which is characterized in that it includes the following steps：
By formula (II) compound and formula (III) compound, in the presence of nonpolar solvent and the bis- (2- oxos -3- of condensing agent are added
Oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride, meet needs with excessive formula (III) compound, at -5 DEG C~40 DEG C, with or without pressure condition
Under be stirred to react 2.5~30 hours, obtain formula (I) compound,
Wherein：
The definition of R and X is the same as claim 1.
4. the preparation method of formula (I) compound according to claim 3, which is characterized in that the nonpolar solvent is selected from
Dichloromethane, chloroform, tetrahydrofuran, dioxane, hexamethylene.
5. compound shown in formula described in claims 1 or 2 (I) is preparing the application in treating tuberculosis.
6. the application of claim 5, which is characterized in that the tuberculosis is selected from active tuberculosis, single resistant tuberculosis, how resistance to
Medicine tuberculosis and extensive multi-drug resistance tuberculosis.
7. the application of claim 5, which is characterized in that the tuberculosis is selected from the outer tuberculosis of pulmonary tuberculosis, lung.
8. a kind of pharmaceutical composition, which is characterized in that using compound described in claims 1 or 2 as active constituent.
9. pharmaceutical composition according to claim 8, which is characterized in that the pharmaceutical composition is prepared into any pharmaceutical
Dosage form.
10. pharmaceutical composition according to claim 9, which is characterized in that the dosage form is selected from：Tablet, capsule, particle
Agent, syrup, powder-injection, injection.
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| US3995044A (en) * | 1974-06-14 | 1976-11-30 | Bayer Aktiengesellschaft | Pyridine carboxylic acid amides for mycobacterium infections |
| DE10158057B4 (en) * | 2001-11-27 | 2005-03-31 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Medicines for the treatment of infectious diseases, in particular tuberculosis and malaria |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3995044A (en) * | 1974-06-14 | 1976-11-30 | Bayer Aktiengesellschaft | Pyridine carboxylic acid amides for mycobacterium infections |
| DE10158057B4 (en) * | 2001-11-27 | 2005-03-31 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Medicines for the treatment of infectious diseases, in particular tuberculosis and malaria |
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