CN106543106A - 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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- 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
- C07D211/08—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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- 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
- C07D211/08—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, its preparation method and medical usage and the antitubercular pharmaceutical composition with which as effective ingredient shown in formula (I).More particularly, it relates to N benzyl benzamide compounds, the substituent group in its benzyl para-position is nitrogen heterocyclic ring fragment, wherein, in formula (I), R represents trifluoromethyl, nitro；X represents 4 thio-morpholinyls, 2 base of octahydro 2H iso-indoles, 2 base of isoindoline, 4 substituted piperidine, 1 base, (4 substituted-phenyl) piperidinyl-1 base, (4 substituted-phenyl) 1 base of piperazine.
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 class N- benzyl -3-
Nitro -5- trifluoromethyl benzamides and N- benzyl -3,5- dinitrobenzamide class compounds, the replacement in its benzyl para-position
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 the serious harm human health caused by mycobacterium tuberculosis (MTB) serious infectious diseases it
One.From the eighties in 20th century, drug resistance TB, the especially sickness rate of multi-drug resistant TB (MDR-TB) constantly rise and TB with
HIV/AIDS combines makes TB epidemic situations rise once again, becomes great public health problem and the social problem of global concern.According to system
Meter, the whole world have 8,000,000 newly-increased TB patients every year, and nearly 3,000,000 people dies from tuberculosis, and nearly 1/3 population carries latent form tubercule bacillus, tool
There is potential initiation potential.Traditional anti-TB medicines, such as streptomycin, isoniazid, rifampicin, ethambutol and pyrazinamide etc. join
Sharing medicine can make more than 85% first control lunger's recovery from illness, but there is treatment cycle length (more than 6 months) and to MDR-TB
Invalid shortcoming, while the effect to latent form MTB is not strong, therefore researches and develops anti-TB new drugs, realizes the effectively treatment to TB with control
Extremely urgent (external medicine-antibiotic the fascicle 2009,30 (1) of system：19-24).
Fortunately, quinoline (ATP is reached as the 1st over the nearly 40 years anti-TB new drugs shellfish with brand-new mechanism of action
Synthetase inhibitors) it is approved by the fda in the United States for treating MDR-TB in 2012.By this inspiration, multiple big systems global in recent years
Medicine company and research unit increase the R＆D intensity of Antituberculous new drug, and disclosed report is some with different mechanism of action
Tuberculosis candidate compound.These candidate compounds are at present or in clinical experimental stage or in the preclinical study stage.
2011, Switzerland's scientist's macha Lip river watt etc. disclosed the 4H- benzos that a class 2- bit substituent is piperazine -1- bases
The synthesis of [e] [1,3] thiazine -4- ketone compounds and anti-tubercular (CN 201180055813.5).Which represents thing
PBTZ169 have outstanding inside and outside wide spectrum anti-tubercular (EMBO Mol Med, 2014,6：372–383).PBTZ169 in
I phase clinical researches are entered in Russia within 2016.
Present inventor has performed extensive study, by 4H- benzos [e] [1, the 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- dinitro benzene first
Amides compound, and determine their anti-tubercular.Finally found that, in the benzyl para-position 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, the compound of (4- substituted-phenyls) piperazine -1- bases have unexpected strong anti-tubercular, with
PBTZ169 and a line antitubercular agent isoniazid are compared with rifampicin, with more superior anti-tubercular.
The content of the invention
It is an object of the invention to provide the N- benzyl benzamide compounds that a class is represented by logical formula (I),
Wherein：
R represents CF3、NO2；
X is selected from following nitrogen heterocyclic ring fragment：
Y represents F, Cl, CF3、OCF3、OCH3；Z represents CH, N.
The present invention specifically includes following compound：
3- nitro -5- trifluoromethyl-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [(4- thio-morpholinyls) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (octahydro -2H- iso-indoles -2- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (isoindoline -2- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- fluorine resources -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- Chloperastine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- trifluoromethoxy piperidin-1-yls) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- methoxy piperide -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- chlorphenyls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- trifluoromethyls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperazine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- chlorphenyls) piperazine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- trifluoromethyls) piperazine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperazine -1- bases) benzyl] Benzoylamide.
Preferably, N- benzyls benzamide compound is selected from：
3- nitro -5- trifluoromethyl-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [(4- thio-morpholinyls) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (octahydro -2H- iso-indoles -2- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperazine -1- bases) benzyl] Benzoylamide.
The invention further relates to the preparation method of formula (I) compound, as shown in reaction scheme 1.
Reaction scheme 1：
By formula II compound and formula (III) compound, in the presence of non-polar solven and double (the 2- oxygen of condensing agent are added
Generation -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride (BOP-Cl), needs are met with excessive formula (III) compound, at -5 DEG C～40 DEG C,
With or without stirring reaction under pressure condition 2.5～30 hours, formula (I) compound is obtained,
In reaction scheme 1, R and X are defined as the aforementioned.
Condensing agent is added in non-polar solven, make formula (II) compound and formula (III) compound by condensation reaction come
Prepare formula (I) compound.
Dichloromethane, chloroform, tetrahydrofuran, dioxane or hexamethylene, institute are selected from for this non-polar solven for reacting
The condensing agent stated is selected from double (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides (BOP-Cl).
Formula (II) compound as starting material is known compound in the present invention, and there is supply of commodities the country.Formula (III)
Compound is also known compound, and the method with reference to known in existing publication is easily achieved, 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 the tuberculosis compositionss containing formula as defined above (I) compound as active component.Medicine
The compounds of this invention that compositions contain weight ratio in the composition is 0.1～99.9%, and pharmaceutically acceptable carrier exists
Weight ratio in compositionss is 0.1～99.9%.Pharmaceutical composition is present to be adapted to medicinal dosage form.The medicine of the present invention
Compositionss can be prepared into any pharmaceutically useful dosage form.Preferably, medicinal preparation be tablet, sugar coated tablet, film coated tablet,
Enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, powder.
The pharmaceutical composition of the present invention, as dosage form, per agent in the effective dose of the compounds of this invention that contains be 0.1
～1000mg, it is described to refer to each preparation unit per agent, such as tablet per piece, per of capsule, can also refer to and each take agent
Amount, such as each takes 100mg.
The pharmaceutical composition of the present invention is in the solid for being prepared into powder, tablet, dispersible powder, capsule, cachet form
During pharmaceutical preparation, solid carrier can be used.The solid carrier that can be used is preferably selected from diluent, flavoring agent, solubilizing agent, lubrication
One or more material in agent, suspending agent, binding agent, extender etc., or can be encapsulating substance.Suitable solid carrier includes
Magnesium carbonate, magnesium stearate, Pulvis Talci, sucrose, Lactose, pectin, dextrin, starch, gelatin, methylcellulose, carboxymethyl cellulose
Sodium, cocoa butter etc..Best oral administration solid system is represented as they are easy to administration, tablet, powder, cachet and capsule etc.
Agent.
Homogeneous for ease of administration and dosage, it is particularly advantageous that said medicine preparation is configured to dosage unit form.
The dosage unit form of preparation refers to the physical separation unit for being adapted as single dose, and each unit contains that generation is desired to be controlled
The active component of the scheduled volume for calculating of therapeutic effect.This dosage unit form can be packaged form, such as tablet, capsule or dress
Powder in tubule or bottle.
Although the amount of contained active component can change in dosage unit form, selected active component is typically based on
Effect, is adjusted in the range of 1～800mg.
When formula (I) reactive compound of the present invention is used as the medicine for the treatment of m tuberculosis infection, preferably first
Stage gives the amount of 6～14mg/kg body weight.But dosage can be with sick human needs, the seriousness of the infection to be treated, institute
Select compound etc. and change.
Those skilled in the art can determine the preferred dose for being suitable to certain situation according to a conventional method.Typically, start what is treated
Amount is then gradually increased dosage, until reaching optimum therapeuticing effect less than the optimal dose of active component.Rise for convenience
See, total daily dose can be divided into several parts, fraction time administration.
The present invention also provides compound shown in formula (I) or the pharmaceutical composition containing the compound and is preparing treatment tuberculosis
Medicine in application.
Tuberculosis of the present invention include active tuberculosis, single resistant tuberculosis, many resistant tuberculosis and extensively resistance to
Multiple medicines tuberculosis.
Tuberculosis of the present invention include the outer tuberculosis of pulmonary tuberculosis, lung.
As described above, the compounds of this invention to the activity of mycobacterium tuberculosis equivalent to or be better than control compound
PBTZ169 and a line antitubercular agent isoniazid and rifampicin.For example, 2,3,7 and 14 compound of embodiment is to tuberculosis branch bar
The external activity of bacterium type strain H37Rv ATCC 27294 is compound PBTZ169, isoniazid and rifampicin >=2 times, to facing
The external activity of bed separation strains MDR-MTB 20161 (to rifampicin and Isoniazid-resistant) is the 2 of compound PBTZ169->7 times.
The compound phase of the present invention for existing product, the better efficacy in terms of tuberculosis, active higher, side effect
Lower, good stability, synthesis technique are simpler, and cost is substantially reduced, and are adapted to large-scale production, and the present invention prepares medicine
The features such as there is high income and high purity also.
Specific embodiment
In the examples below, the present invention will more specifically be explained.It should be understood that the following example is intended to illustrate this
It is bright and any restriction is not constituted to the scope of the present invention.
1 3- nitro -5- trifluoromethyl-N- of embodiment [4- (4- trifluoromethyl piperidine -1- bases) benzyl] Benzoylamide
Under nitrogen protection, by 3- nitro -5- (trifluoromethyl) benzoic acid (0.23g, 0.1mmol), 4- (4- (trifluoromethyl)
Piperidin-1-yl) aniline, double (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) stirring reaction 2h at room temperature.Reaction terminates, washing
(25ml), then organic layer is washed with saturated nacl aqueous solution.Concentration, residue Jing column chromatography for separation obtain off-white powder
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- dinitro-N- [(4- thio-morpholinyls) benzyl] Benzoylamide
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- dinitro-N- [4- (octahydro -2H- iso-indoles -2- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (isoindoline -2- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (4- fluorine resources -1- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (4- Chloperastine -1- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (4- trifluoromethoxy piperidin-1-yls) benzyl] Benzoylamide
With the preparation method of 1 compound of embodiment, 3,5- nitre, two yl benzoic acid and 4- (4- trifluoromethoxy piperidin-1-yls)
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- dinitro-N- [4- (4- methoxy piperide -1- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (4- (4- fluorophenyls) piperidin-1-yl) benzyl] Benzoylamide
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- dinitro-N- [4- (4- (4- chlorphenyls) piperidin-1-yl) benzyl] Benzoylamide
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- dinitro-N- [4- (4- (4- trifluoromethyls) piperidin-1-yl) benzyl] Benzoylamide
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- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperidin-1-yl) benzyl] Benzoylamide
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- dinitro-N- [4- (4- (4- fluorophenyls) piperazine -1- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (4- (4- chlorphenyls) piperazine -1- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (4- (4- trifluoromethyls) piperazine -1- bases) benzyl] Benzoylamide
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- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperazine -1- bases) benzyl] Benzoylamide
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 determining which 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 rifampicin and Isoniazid-resistant)
Come what is represented.In this experiment, compared with candidate compound PBTZ169 and a line antitubercular agent isoniazid and rifampicin
Medicine.Minimal inhibitory concentration is determined as follows：Aseptic 48 orifice plate (the special microtest plate of tulase quick medicine-sensitive), by susceptibility
EXPERIMENTAL DESIGN requires that each hole is separately added into the medicine diluted with 2 times of concentration cultures (improvement Michaelis 7H9 fluid mediums).Respectively
Compound makes the first solution of debita spissitudo, is diluted to two times of concentration of each compound used therefor, Mei Zhonghua with culture medium (2 ×)
Each 10 gradients of compound, add 48 orifice plates per 100 μ L of hole, and 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 pore fungi amount- 3mg.2 growth Positive control wells without antimicrobial drug are all provided with per plate and two growth feminine genders with distilled water substitutive medium are right
According to hole, surrounding adhesive tape sealing after 48 orifice plates are added a cover 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, it was observed that when both have clear and definite difference, the quantity and form to each test hole bacterial growth
Observed, judge suppression or drug resistance and record result, observed and recorded is once confirmed again after the 7th day.Asepsis growth it is right
Minimal inhibitory concentration (MIC) is according to the minimum concentration of contained drug in hole.Measurement result is listed in table 1.
External activity of the 1 section Example compound of table to 2 plants of mycobacterium tuberculosis
MTBa:MTB H37Rv ATCC 27294
MDR-MTBb：MDR-MTB 20161 (to rifampicin and Isoniazid-resistant)
The external activity of of the present invention part of compounds is enumerated in above-mentioned table only, other compound structures of the invention are similar,
It is with the external activity effect same or like with above-claimed cpd, numerous to list herein.
Biological Examples 1
Oral Acute Toxicity is tested
To determine 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 variable concentrations is orally awarded male mice by acute toxicity testing, and dosage is 0.1ml/10g
Body weight, counted after 7 days dead Mus amount respectively, calculates the median lethal dose(LD 50) (LD of each compound with Bliss programs50).As a result it is listed in table 2
In.
The Mouse oral acute toxicity of 2 embodiment 1 of table and 2 compounds
Test result indicate that, these toxicity of compound are very low, are especially suitable for medicinal.
Compositionss embodiment
1 coated tablet of embodiment
Core formulation：
Mentioned component mix homogeneously is taken, sieve after granulation granulate, dry, tabletting makes 100 labels.Coating fluid prescription：
OPADRY (Opadry) 5g, 80% appropriate amount of ethanol coating.
2 capsule of embodiment
Prescription：
Preparation method：
Recipe quantity supplementary material is taken, is sieved respectively, added 5% polyvinylpyrrolidone alcohol liquid and Tween 80 soft material, use 20
Mesh sieve is pelletized, and dries at 15 DEG C of room temperature, adds sodium lauryl sulphate, mix homogeneously to load No. 0 stomach colloidal sol 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, adds appropriate dextrin, steviosin, and dry granulation, granulate, subpackage are obtained final product.
7 injection of embodiment
The compound 150g of Example 7 is dissolved in water, another Sodium Chloride, ethylparaben heating water dissolution, mixes
It is even, adjust pH value 5-7.Water for injection is diluted to 1000ml, is filtered with hollow-fibre membrane, fill, and sterilizing is obtained final product.
10 freeze-dried powder of embodiment
The compound 150g of Example 10 is dissolved in water, and separately adds Mannitol 500g heating water dissolution, mixes, water for injection
5000ml is diluted to, is filtered with hollow-fibre membrane, fill, sterilizing, lyophilizing obtain final product freeze-dried powder.
14 drop pill of embodiment
The compound 20g of Example 14 is standby as crude drug；Drop pill substrate 200g is weighed, 80 DEG C of thawings are heated to,
Stir；Added raw materials in excipient matrix while stirring, stirring 30min is allowed to uniform, keep fluid temperature to be not less than 60
℃；The medicinal liquid for preparing is injected in pill dripping machine, drop pill is dripped into, 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 fragment：
Wherein, Y represents F, Cl, Br, CF3、OCF3、OCH3；Z represents CH, N.
2. compound shown in formula (I) according to claim 1, it is characterised in that its compound is：
3- nitro -5- trifluoromethyl-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [(4- thio-morpholinyls) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (octahydro -2H- iso-indoles -2- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (isoindoline -2- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- fluorine resources -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- Chloperastine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- trifluoromethyl piperidine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- trifluoromethoxy piperidin-1-yls) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- methoxy piperide -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- chlorphenyls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- trifluoromethyls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperidin-1-yl) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- fluorophenyls) piperazine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- chlorphenyls) piperazine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- trifluoromethyls) piperazine -1- bases) benzyl] Benzoylamide；
3,5- dinitro-N- [4- (4- (4- Trifluoromethoxyphen-ls) piperazine -1- bases) benzyl] Benzoylamide.
3. the method that one kind prepares formula described in claim 1 or 2 (I) compound, it is characterised in which comprises the steps：
By formula II compound and formula (III) compound, in the presence of non-polar solven and the double (2- oxo -3- of condensing agent are added
Oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (BOP-Cl), needs are met with excessive formula (III) compound, at -5 DEG C～40 DEG C, with or without
Stirring reaction 2.5～30 hours under pressure condition, obtain formula (I) compound,
Wherein：
The definition of R and X is with claim 1.
4. the preparation method of formula (I) compound according to claim 3, it is characterised in that described non-polar solven is selected from
Dichloromethane, chloroform, tetrahydrofuran, dioxane, hexamethylene.
5. application of the compound shown in formula described in claim 1 or 2 (I) in treatment tuberculosis are prepared.
6. application of the pharmaceutical composition containing compound described in claim 1 or 2 in treatment tuberculosis are prepared.
7. the application of claim 5 or 6, it is characterised in that the tuberculosis include active tuberculosis, single resistant tuberculosis,
Many resistant tuberculosis and extensive multi-drug resistance tuberculosis.
8. the application of claim 5 or 6, it is characterised in that the tuberculosis include the outer tuberculosis of pulmonary tuberculosis, lung.
9. the pharmaceutical composition with compound described in claim 1 or 2 as active component.
10. pharmaceutical composition according to claim 9, it is characterised in that the pharmaceutical composition is prepared into any pharmaceutically acceptable
Dosage form, preferred dosage form is selected from：Tablet, capsule, granule, syrup, injectable powder, injection.
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| CN109691450A (en) * | 2018-12-28 | 2019-04-30 | 利民化工股份有限公司 | The purposes of N- benzyl benzamide compound and combinations thereof, mix preparation |
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| CN107674014A (en) * | 2017-09-28 | 2018-02-09 | 北京市结核病胸部肿瘤研究所 | 3 containing isoindoline fragment, 5 dinitrobenzamide class compounds and preparation method thereof |
| CN107674014B (en) * | 2017-09-28 | 2020-01-17 | 北京市结核病胸部肿瘤研究所 | 3, 5-dinitrobenzamide compound containing isoindoline fragment and preparation method thereof |
| CN109691450A (en) * | 2018-12-28 | 2019-04-30 | 利民化工股份有限公司 | The purposes of N- benzyl benzamide compound and combinations thereof, mix preparation |
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