CN105669664B - Benzothiazine -4- ketone compounds containing basic nitrogen heterocyclic fragments and preparation method thereof - Google Patents
Benzothiazine -4- ketone compounds containing basic nitrogen heterocyclic fragments and preparation method thereof Download PDFInfo
- Publication number
- CN105669664B CN105669664B CN201610094025.1A CN201610094025A CN105669664B CN 105669664 B CN105669664 B CN 105669664B CN 201610094025 A CN201610094025 A CN 201610094025A CN 105669664 B CN105669664 B CN 105669664B
- Authority
- CN
- China
- Prior art keywords
- ketone
- nitro
- benzo
- trifluoromethyl
- thiazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The present invention relates to formula (I) and (I/) shown in the benzothiazine -4- ketone compounds containing basic nitrogen heterocyclic fragments, preparation method and medical usage and using it as the antitubercular pharmaceutical composition of effective component.More particularly, the present invention relates to a kind of 6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone compounds, its 2- bit substituent is 1- azacycloalkyl or diazacyclo alkyl containing amido, wherein, R represents the alkyl of H, 1-4 C atoms, the naphthenic base of 4-7 C atom, phenyl, substituted-phenyl；R1 represents the naphthenic base of the alkyl of H, 1-3 C atoms, 3-6 C atom；R2 represents the alkyl of H, 1-4 C atoms, the naphthenic base of 4-7 C atom, phenyl, substituted-phenyl；N1 represents 0-1；N2 represents 1-3；N3 represents 1,3.
Description
Technical field
The invention belongs to medicinal chemistry arts, it is related to the benzo thiophene containing basic nitrogen heterocyclic fragments with anti-tubercular
Piperazine -4- ketone compounds and preparation method thereof, and contain their antitubercular pharmaceutical composition；More specifically, of the invention
It is related to 6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone compounds, 2- bit substituent is containing amido
1- azacycloalkyl or diazacyclo alkyl.
Background technique
Tuberculosis (TB) be by seriously endanger caused by mycobacterium tuberculosis (MTB) serious infectious diseases of human health it
One.Since the 1980s, the disease incidence of drug resistance TB, especially multi-drug resistant TB (MDR-TB) constantly rise and TB with
HIV/AIDS, which is combined, rises TB epidemic situation once again, becomes the great public health problem and social concern of global concern.According to system
There are 8,000,000 newly-increased TB patients in meter, the whole world every year, and nearly 3,000,000 people dies of tuberculosis, and nearly 1/3 population carries latent form tubercle bacillus, tool
There is potential initiation potential.Traditional anti-TB drug, 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 long (being greater 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 drug is 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 drug 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.
2007, it was 4,4- dialkoxy piperidines -1- that Switzerland scientist Ma Kaluowa etc., which discloses a kind of 2- bit substituent,
The synthesis of 4H- benzo [e] [1,3] thiazine -4- ketone compounds of base and anti-tubercular (2007/134625 A1 of WO).Its
Represent object BTZ043 with external wide spectrum anti-tubercular (Antimicrob Agent Chemother, 2010,54 (4):
1616-1618；2012,56 (7): 3984-3985), but because water-soluble poor, the activity in vivo of BTZ043 can not show a candle to be expected
(EMBO Mol Med, 2014,6:372-383).
2011, Switzerland scientist Ma Kaluowa etc. further disclosed the 4H- that a kind of 2- bit substituent is piperazine -1- base
The synthesis of benzo [e] [1,3] thiazine -4- ketone compounds and anti-tubercular (CN 201180055813.5).It represents object
PBTZ169 equally has an external wide spectrum anti-tubercular, activity in vivo be significantly stronger than BTZ043 (EMBO Mol Med, 2014,
6:372-383).As second generation benzothiazine -4- ketone treating tuberculosis candidate, it is preclinical that PBTZ169 has been approached completion at present
Research.
Present inventor has performed extensive research, design synthesis 2- contains the benzo thiophene of various basic nitrogen heterocyclic fragments
Piperazine -4- ketone compounds, and determine their anti-tubercular.It finally found that, 2- reported in the literature different from the past takes
Dai Ji is the 6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] of the 1- azacycloalkyl containing amido or diazacyclo alkyl
Thiazine -4- ketone compounds have unexpected strong anti-tubercular, with similar benzothiazine -4- ketone candidate compound
PBTZ169 and a line anti-tubercular drug isoniazid are compared with rifampin, have more superior anti-tubercular.
Summary of the invention
The object of the present invention is to provide one kind by logical formula (I) and (I/) indicate the 6- trifluoro containing basic nitrogen heterocyclic fragments
Methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone compounds,
Wherein:
R represents the alkyl of H, 1-4 C atoms, the naphthenic base of 4-7 C atom, phenyl, substituted-phenyl in formula (I)；R1 generation
The naphthenic base of the alkyl of H, 1-3 C atoms of table, 3-6 C atom；N1 represents 0-1；N2 represents 1-3.Formula (I/) in R2 represent H,
The alkyl of 1-4 C atom, the naphthenic base of 4-7 C atom, phenyl, substituted-phenyl；N3 represents 1,3.
The present invention specifically includes following compound:
2- [3- (cyclohexyl methyl) (methyl) amido azetidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
2- [3- (to mehtoxybenzyl) (ethyl) amido azetidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone
2- [3- (cyclohexyl methyl) (methyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
2- [3- (cyclohexyl methyl) (cyclopropyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone
2- [3- (cyclopentyl-methyl) (cyclobutyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone
2- [3- (neopentyl) (ethyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3]
Thiazine -4- ketone
2- [4- (methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone
2- [4- (ethyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone
2- [4- (cyclohexyl methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone
2- [4- (benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone
2- [4- (to trifluoromethylbenzel) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone
2- [4- (to trifluoromethoxy benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone
2- [4- (to trifluoromethoxy benzyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone
2- [4- (cyclohexyl methyl) (cyclopenta) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
2- [4- (neopentyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone
2- [4- (cyclopentyl-methyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone
2- [4- (cyclohexyl methyl) (cyclopropyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
2- [3- (cyclohexyl methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone
2- [3- (to trifluoromethoxy benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone
2- [(3- ethyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [(3- cyclopentyl-methyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -
4- ketone
2- [(3- cyclohexyl methyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -
4- ketone
2- [3- (to trifluoromethoxy benzyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone
2- [(3- CycloheptylmethyI) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -
4- ketone
2- [(3- neopentyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [(4- methyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -
4- ketone
2- [(4- cyclopentyl-methyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone
2- [(4- cyclohexyl methyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone
2- [4- (benzyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -
4- ketone
2- [4- (to trifluoromethoxy benzyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone
2- [4- (to trifluoromethylbenzel) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone
The invention further relates to formula (I) and (I/) compound preparation method, respectively as shown in reaction route 1 and 2.
Reaction route 1:
In reaction route 1, R, R1, n1 and n2 are defined as the aforementioned.
Reaction route 2:
In reaction route 2, R2 and n3 are defined as the aforementioned.
Acid binding agent is added in protonic solvent, make formula (II) compound respectively with formula (III) and (III/) compound is logical
Condensation reaction is crossed to prepare formula (I) and (I/) compound.Protonic solvent for this reaction is selected from water, alcohol or alcohol-water mixing
Solvent；The acid binding agent is selected from triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Formula (II) compound as starting material is known compound in the present invention, and with reference to known in existing publication
Method can easily be made, such as CN 201180055813.5.
It is used as the formula (III) and (III of starting material in the present invention/) compound is known compound, home or overseas has
Supply of commodities.
The present invention also provides contain formula as defined above (I) and (I/) treating tuberculosis combination of the compound as active constituent
Object.The weight ratio of the compounds of this invention that pharmaceutical composition contains in the composition is 0.1~99.9%, pharmaceutically acceptable load
The weight ratio of body in the composition is 0.1~99.9%.Pharmaceutical composition is to be suitble to medicinal dosage form to exist.Of the invention
Pharmaceutical composition can be prepared into any pharmaceutical dosage form.Preferably, medicinal preparation is tablet, sugar coated tablet, film-coating
Tablet, enteric coated tablet, sustained-release tablet, capsule, hard capsule, soft capsule, Duracaps, powder.
Pharmaceutical composition of the 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.
Pharmaceutical composition of the invention be prepared into pulvis, tablet, dispersible pulvis, capsule, cachet form solid
When pharmaceutical preparation, solid carrier can be used.Workable solid carrier is preferably selected from diluent, flavoring agent, solubilizer, lubrication
One of agent, suspending agent, adhesive, swelling agent etc. or many kinds of substance, 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.
As formula (I) of the invention or (I/) reactive compound be used as treatment mycobacterium tuberculosis infection drug when, preferably
Give the amount of 6~14mg/kg weight in the first stage.But dosage can with sick human needs, the infection to be treated it is tight
Principal characteristic, selected compounds etc. and change.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Generally, start treatment
Amount is lower than the optimal dose of active constituent, dosage is then gradually increased, until reaching optimum therapeuticing effect.It rises for convenience
See, total daily dose can be divided into several parts, be administered in several times.
The present invention also provides formula (I) and (I/) shown in compound or pharmaceutical composition containing the compound treated in preparation
Application in tuberculosis.
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 waits the activity of mycobacterium tuberculosis much higher than similar benzothiazine -4- ketone
Select compound PBTZ169 and a line anti-tubercular drug isoniazid and rifampin.For example, 3,8,11,18 and 27 compound of embodiment
External activity to mycobacterium tuberculosis type strain H37Rv ATCC 27294 is compound PBTZ169, isoniazid and rifampin
2-10 times, the external activity to clinical separation strain MDR-MTB 20161 (to rifampin and Isoniazid-resistant) is also compound
2-10 times of PBTZ169.
The compound of the present invention is for existing product, and curative effect is better in terms for the treatment of tuberculosis, active higher, side effect
Lower, synthesis process operation is also simpler, effectively reduces cost, and is suitble to large-scale production.
Specific embodiment
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 2- of embodiment [3- (cyclohexyl methyl) (methyl) amido azetidine -1- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
By 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone (0.16g, 0.5mmol)
It is dissolved in dehydrated alcohol (8mL), is added triethylamine (0.10g, 1.0mmol), 3- (cyclohexyl methyl) (methyl) amido azete is added dropwise
Dehydrated alcohol (10mL) solution of pyridine (0.18g, 1.0mmol), is stirred to react 3h in 60 DEG C, filtering, filtrate decompression concentration, remaining
Object obtains yellow solid (yield 51%) through column chromatography for separation.
1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),3.73–3.36(m,5H),2.26(s,3H),
2.18-2.09(m,2H),1.90–1.56(m,5H),1.35–1.13(m,6H).
MS-ESI(m/z):457(M+H)+。
2 2- of embodiment [3- (to mehtoxybenzyl) (ethyl) amido azetidine -1- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 3- (to mehtoxybenzyl) (ethyl) amido azetidine and 2- first sulphur
The condensation of base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 55%).
1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),7.25-7.02(m,4H),3.92(s,3H),
3.75–3.41(m,7H),2.64(q,2H),1.02(t,3H).
MS-ESI(m/z):495(M+H)+。
3 2- of embodiment [3- (cyclohexyl methyl) (methyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 3- (cyclohexyl methyl) (methyl) amino-pyrrolidine and 2- methyl mercapto -6-
The condensation of trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 53%), mp:126-129
℃。
1H NMR(500MHz,CDCl3)δ9.17(s,1H),8.78(s,1H),4.36–4.18(m,4H),4.15–4.03
(m,1H),3.91(s,3H),3.80–3.61(m,2H),1.89–1.45(m,7H),1.33–1.13(m,6H).
MS-ESI(m/z):471(M+H)+。
4 2- of embodiment [3- (cyclohexyl methyl) (cyclopropyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 3- (cyclohexyl methyl) (cyclopropyl) amino-pyrrolidine and 2- methyl mercapto-
The condensation of 6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 50%).
1H NMR(500MHz,CDCl3)δ9.17(s,1H),8.78(s,1H),2.92–2.73(m,5H),2.42-2.21
(m,2H),1.89–1.50(m,7H),1.44–1.25(m,7H),0.67–0.42(m,4H).
MS-ESI(m/z):497(M+H)+。
5 2- of embodiment [3- (cyclopentyl-methyl) (cyclobutyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 3- (cyclopentyl-methyl) (cyclobutyl) amino-pyrrolidine and 2- methyl mercapto-
The condensation of 6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 49%).
1H NMR(500MHz,CDCl3)δ9.17(s,1H),8.78(s,1H),3.10–2.75(m,6H),2.45-2.23
(m,2H),2.15–1.90(m,6H),1.74–1.35(m,11H).
MS-ESI(m/z):497(M+H)+。
6 2- of embodiment [3- (neopentyl) (ethyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 3- (neopentyl) (ethyl) amino-pyrrolidine and 2- methyl mercapto -6- trifluoro
The condensation of methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 51%).
1H NMR(500MHz,CDCl3)δ9.17(s,1H),8.78(s,1H),3.12–2.77(m,5H),2.46-2.21
(m,2H),2.40(q,2H),2.28(s,2H),1.74-1.52(m,2H),1.02(t,3H),0.94(s,9H).
MS-ESI(m/z):459(M+H)+。
7 2- of embodiment [4- (methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (methyl) (methyl) amino piperidine and 2- methyl mercapto -6- fluoroform
The condensation of base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 48%).
1H NMR(500MHz,CDCl3) δ 8.99 (s, 1H), 8.72 (s, 1H), 3.01-2.91 (m, 4H), 2.63-2.51
(m,1H),2.26(s,6H),1.71-1.44(m,4H).
MS-ESI(m/z):403(M+H)+。
8 2- of embodiment [4- (ethyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (ethyl) (ethyl) amino piperidine and 2- methyl mercapto -6- fluoroform
The condensation of base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 51%).
1H NMR(500MHz,CDCl3) δ 8.99 (s, 1H), 8.72 (s, 1H), 3.03-2.94 (m, 4H), 2.65-2.52
(m,5H),1.69-1.44(m,4H),1.02(t,6H).
MS-ESI(m/z):431(M+H)+。
9 2- of embodiment [4- (cyclohexyl methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (cyclohexyl methyl) (methyl) amino piperidine and 2- methyl mercapto -6- three
The condensation of methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 52%), mp:146-149 DEG C.
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),2.94(s,3H),2.79(s,2H),2.71–
2.35(m,5H),2.03–1.71(m,8H),1.71(s,1H),1.36–0.97(m,6H).
MS-ESI(m/z):485(M+H)+。
10 2- of embodiment [4- (benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (benzyl) (methyl) amino piperidine and 2- methyl mercapto -6- fluoroform
The condensation of base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 52%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),7.33-7.23(m,5H),3.66(s,2H),
3.01-2.91(m,4H),2.69-2.61(m,1H),2.26(s,3H),1.69-1.50(m,4H).
MS-ESI(m/z):479(M+H)+。
11 2- of embodiment [4- (to trifluoromethylbenzel) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (to trifluoromethylbenzel) (methyl) amino piperidine and 2- first sulphur
The condensation of base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 53%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),7.50-7.16(m,4H),3.66(s,2H),
3.01-2.91(m,4H),2.69-2.61(m,1H),2.26(s,3H),1.69-1.50(m,4H).
MS-ESI(m/z):547(M+H)+。
12 2- of embodiment [4- (to trifluoromethoxy benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (to trifluoromethoxy benzyl) (methyl) amino piperidine and 2- first
The condensation of sulfenyl -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 51%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),7.25-6.90(m,4H),3.71(s,2H),
3.11-2.99(m,4H),2.71-2.65(m,1H),2.32(s,3H),1.74-1.56(m,4H).
MS-ESI(m/z):563(M+H)+。
13 2- of embodiment [4- (to trifluoromethoxy benzyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (to trifluoromethoxy benzyl) (ethyl) amino piperidine and 2- first
The condensation of sulfenyl -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 52%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),7.26-7.01(m,4H),3.69(s,2H),
3.15-2.99(m,4H),2.77-2.69(m,3H),2.32(s,3H),1.76-1.58(m,4H),1.02(t,3H).
MS-ESI(m/z):577(M+H)+。
14 2- of embodiment [4- (cyclohexyl methyl) (cyclopenta) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (cyclohexyl methyl) (cyclopenta) amino piperidine and 2- methyl mercapto -6-
The condensation of trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 52%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),3.15-2.99(m,4H),2.65-2.63
(m,2H),2.11-2.08(m,2H),1.72-1.68(m,6H),1.56-1.46(m,10H),1.43-1.27(m,7H).
MS-ESI(m/z):539(M+H)+。
15 2- of embodiment [4- (neopentyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (neopentyl) (methyl) amino piperidine and 2- methyl mercapto -6- fluoroform
The condensation of base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 53%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),3.15-2.99(m,4H),2.65-2.63
(m,1H),2.28-2.26(m,5H),1.69-1.44(m,4H),0.95(s,9H).
MS-ESI(m/z):459(M+H)+。
16 2- of embodiment [4- (cyclopentyl-methyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (cyclopentyl-methyl) (ethyl) amino piperidine and 2- methyl mercapto -6- three
The condensation of methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 52%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),3.15-2.99(m,4H),2.65-2.63
(m,3H),2.11-2.09(m,2H),1.74-1.56(m,6H),1.53-1.35(m,7H),1.02(t,3H).
MS-ESI(m/z):485(M+H)+。
17 2- of embodiment [4- (cyclohexyl methyl) (cyclopropyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (cyclohexyl methyl) (cyclopropyl) amino piperidine and 2- methyl mercapto -6-
The condensation of trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 48%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),3.02-2.92(m,4H),2.65-2.63
(m,1H),2.11-2.09(m,2H),1.71-1.52(m,6H),1.50-1.32(m,6H),0.67-0.42(m,4H).
MS-ESI(m/z):511(M+H)+。
18 2- of embodiment [3- (cyclohexyl methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 3- (cyclohexyl methyl) (methyl) amino piperidine and 2- methyl mercapto -6- three
The condensation of methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 50%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),3.15-2.92(m,2H),2.98-2.94
(m,2H),2.65-2.63(m,1H),2.35-2.32(m,2H),1.71-1.52(m,8H),1.56-1.36(m,8H),0.67-
0.42(m,4H).
MS-ESI(m/z):511(M+H)+。
19 2- of embodiment [3- (to trifluoromethoxy benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 3- (to trifluoromethoxy benzyl) (methyl) amino piperidine and 2- first
The condensation of sulfenyl -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 51%).
1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.72(s,1H),7.25-7.01(m,4H),3.62(s,2H),
3.15-2.92(m,2H),2.98-2.94(m,2H),2.65-2.63(m,1H),2.36(s,3H),1.69-1.43(m,4H).
MS-ESI(m/z):563(M+H)+。
20 2- of embodiment [(3- ethyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone
With the preparation method of 1 compound of embodiment, (3- ethyl) imidazoline and 2- methyl mercapto -6- trifluoromethyl -8- nitro -
The condensation of 4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 51%).
1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.87(s,1H),3.62(s,2H),2.66-2.64(m,
4H),2.48(t,2H),1.02(t,3H).
MS-ESI(m/z):375(M+H)+。
21 2- of embodiment [(3- cyclopentyl-methyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, (3- cyclopentyl-methyl) imidazoline and 2- methyl mercapto -6- trifluoromethyl -
The condensation of 8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 53%).
1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.87(s,1H),3.62(s,2H),2.65(t,2H),2.48
(t,2H),2.09(m,2H),1.74-1.35(m,9H).
MS-ESI(m/z):429(M+H)+。
22 2- of embodiment [(3- cyclohexyl methyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, (3- cyclohexyl methyl) imidazoline and 2- methyl mercapto -6- trifluoromethyl -
The condensation of 8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 54%).
1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.87(s,1H),3.62(s,2H),2.65(t,2H),2.48
(t,2H),2.09(m,2H),1.69-1.53(m,6H),1.50-1.27(m,5H).
MS-ESI(m/z):443(M+H)+。
23 2- of embodiment [3- (to trifluoromethoxy benzyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 3- (to trifluoromethoxy benzyl) imidazoline and 2- methyl mercapto -6- three
The condensation of methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 54%).
1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.87(s,1H),7.25-7.01(m,4H),3.76(s,3H),
3.62(s,3H),2.65(t,2H),2.48(t,2H).
MS-ESI(m/z):521(M+H)+。
24 2- of embodiment [(3- CycloheptylmethyI) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, (3- CycloheptylmethyI) imidazoline and 2- methyl mercapto -6- trifluoromethyl -
The condensation of 8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 55%).
1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.87(s,1H),3.62(s,3H),2.65(t,2H),2.48
(t,2H),2.11-2.09(m,2H),1.71-1.56(m,7H),1.52-1.13(m,6H).
MS-ESI(m/z):457(M+H)+。
25 2- of embodiment [(3- neopentyl) imidazoline -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3]
Thiazine -4- ketone
With the preparation method of 1 compound of embodiment, (3- neopentyl) imidazoline and 2- methyl mercapto -6- trifluoromethyl -8- nitre
The condensation of base -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 51%).
1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.87(s,1H),3.62(s,3H),2.65(t,2H),2.48
(t,2H),2.28(s,2H),0.94(s,9H).
MS-ESI(m/z):417(M+H)+。
26 2- of embodiment [(4- methyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, (4- methyl)-Isosorbide-5-Nitrae-diazepine and 2- methyl mercapto -6- trifluoromethyl -
The condensation of 8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 52%).
1H NMR(500MHz,CDCl3)δ8.98(s,1H),8.68(s,1H),3.19(t,2H),2.78(t,2H),2.65
(t,2H),2.48(t,2H),2.28(s,3H),1.51-1.48(m,2H).
MS-ESI(m/z):389(M+H)+。
27 2- of embodiment [(4- cyclopentyl-methyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, (4- cyclopentyl-methyl)-Isosorbide-5-Nitrae-diazepine and 2- methyl mercapto -6- three
The condensation of methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 51%).
1H NMR(500MHz,CDCl3)δ8.98(s,1H),8.68(s,1H),3.19(t,2H),2.78(t,2H),2.65
(t,2H),2.48(t,2H),2.26-2.10(m,2H),1.74-1.51(m,6H),1.49-1.31(m,5H).
MS-ESI(m/z):457(M+H)+。
28 2- of embodiment [(4- cyclohexyl methyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, (4- cyclohexyl methyl)-Isosorbide-5-Nitrae-diazepine and 2- methyl mercapto -6- three
The condensation of methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 48%), mp:102-104 DEG C.
1H NMR(500MHz,CDCl3)δ9.08(s,1H),8.80(s,1H),4.02(s,2H),2.95(t,2H),2.38–
2.09(m,4H),1.96–1.64(m,8H),1.36–0.98(m,7H).
MS-ESI(m/z):471(M+H)+。
29 2- of embodiment [4- (benzyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (benzyl)-Isosorbide-5-Nitrae-diazepine and 2- methyl mercapto -6- trifluoromethyl -
The condensation of 8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 48%).
1H NMR(500MHz,CDCl3)δ9.08(s,1H),8.80(s,1H),4.11(s,2H),4.02(t,2H),2.95
(t,2H),2.38–2.09(m,4H),1.69–1.66(m,2H).
MS-ESI(m/z):465(M+H)+。
30 2- of embodiment [4- (to trifluoromethoxy benzyl) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (to trifluoromethoxy benzyl)-Isosorbide-5-Nitrae-diazepine and 2- first sulphur
The condensation of base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 46%).
1H NMR(500MHz,CDCl3)δ9.08(s,1H),8.80(s,1H),7.28-7.01(m,4H),3.96(s,2H),
3.61(t,2H),2.95(t,2H),2.38–2.09(m,4H),1.69–1.66(m,2H).
MS-ESI(m/z):549(M+H)+。
31 2- of embodiment [4- (to trifluoromethylbenzel) -1,4- diazepine -1- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
With the preparation method of 1 compound of embodiment, 4- (to trifluoromethylbenzel)-Isosorbide-5-Nitrae-diazepine and 2- first sulphur
The condensation of base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone, obtains yellow solid (yield 52%).
1H NMR(500MHz,CDCl3)δ9.08(s,1H),8.80(s,1H),7.51-7.25(m,4H),3.69(t,2H),
2.95(t,2H),2.38–2.09(m,4H),1.69–1.66(m,2H).
MS-ESI(m/z):533(M+H)+。
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 MTB H37Rv
Minimal inhibitory concentration (MIC, the μ of ATCC 27294 and clinical separation strain MDR-MTB 20161 (to rifampin and Isoniazid-resistant)
G/mL it) indicates.In this experiment, with similar benzothiazine -4- ketone candidate compound PBTZ169 and a line treating tuberculosis
Drug isoniazid and rifampin compare medicine.Minimal inhibitory concentration measures as follows: sterile 48 orifice plate (tulase quick medicine-sensitive
Dedicated microtest plate), by drug sensitive test design requirement, each hole is separately added into 2 times of concentration cultures (improvement Michaelis 7H9 liquid
Body culture medium) diluted drug.The first solution of debita spissitudo is made in each compound, is diluted to culture medium (2 ×) each used
The every 100 μ L of hole of 48 orifice plates, the final concentration difference of investigational agent is added in two times of concentration of compound, each 10 gradients of every kind of compound
For 8,4,2 ... 0.015 μ g/mL.Type strain H37Rv ATCC 27294 and clinical separation strain MDR-MTB 20161, every hole connect
100 μ l of kind, every hole bacterium amount are 4 × 10- 3mg.Every plate be all provided with 2 without antimicrobial growth Positive control wells and two with distillation
The growth negative control hole of water substitutive medium, surrounding is sealed with adhesive tape after 48 orifice plates are covered, and is placed in 37 DEG C of wet box and is incubated
It educates.Growth positive control wells and negative growth control wells are observed after 3rd day, when observing that the two has clear difference, to each examination
The quantity of bacterial growth of verifying and form are observed, and are determined inhibition or drug resistance and are recorded as a result, observing and recording one again after the 7th day
It is secondary to be confirmed.The smallest concentration of contained drug is minimal inhibitory concentration (MIC) in the control wells of asepsis growth.Measurement result
It 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 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 2
Oral Acute Toxicity test
For the Oral Acute Toxicity for measuring the compounds of this invention, 3 compound of embodiment and 11 compound of embodiment are carried out
Acute toxicity testing awards male mice, dosage 0.1ml/ for the solution of the two compounds containing various concentration is oral
10g weight, count dead mouse amount respectively after 7 days, and the median lethal dose (LD of each compound is calculated with Bliss program50).As a result it is listed in
In table 2.
The Mouse oral acute toxicity of 2 compound of embodiment 3 and 11 of table
The experimental results showed that these toxicity of compound are very low, it is very suitable to 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 granulation, dries at 15 DEG C of room temperature, and lauryl sodium sulfate is added, and is uniformly mixed, and is packed into No. 0 glue soluble in the stomach 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 23, is added appropriate dextrin, Steviosin, dry granulation, whole grain, packing to get.
4 injection of embodiment
The compound 150g of Example 2 is dissolved in water, and another sodium chloride, ethyl-para-hydroxybenzoate add hot water dissolving, mixes
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.
5 freeze-dried powder of embodiment
The compound 150g of Example 8 is dissolved in water, and separately plus mannitol 500g adds hot water dissolving, mixes, water for injection
It is diluted to 5000ml, is filtered with hollow-fibre membrane, filling, sterilizing is lyophilized up to freeze-dried powder.
6 dripping pill of embodiment
The compound 20g of Example 1 is spare as bulk pharmaceutical chemicals；Dripping pill matrix 200g is weighed, 80 DEG C of thawings is heated to, stirs
It mixes uniformly；It adds raw materials into excipient matrix while stirring, stirring 30min is allowed to uniformly, fluid temperature be kept to be not less than 60 DEG C；
Prepared medical fluid is injected in pill dripping machine, is dripped into dripping pill.
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, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.
Claims (7)
1. benzothiazine -4- the ketone compounds containing basic nitrogen heterocyclic fragments, specifically:
2- [3- (cyclohexyl methyl) (methyl) amido azetidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3]
Thiazine -4- ketone；
2- [3- (to mehtoxybenzyl) (ethyl) amido azetidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone；
2- [3- (cyclohexyl methyl) (methyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3]
Thiazine -4- ketone；
2- [3- (cyclohexyl methyl) (cyclopropyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone；
2- [3- (cyclopentyl-methyl) (cyclobutyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone；
2- [3- (neopentyl) (ethyl) amino-pyrrolidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone；
2- [4- (methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4-
Ketone；
2- [4- (ethyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4-
Ketone；
2- [4- (cyclohexyl methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone；
2- [4- (benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4-
Ketone；
2- [4- (to trifluoromethylbenzel) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e]
[1,3] thiazine -4- ketone；
2- [4- (to trifluoromethoxy benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone；
2- [4- (to trifluoromethoxy benzyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone；
2- [4- (cyclohexyl methyl) (cyclopenta) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3]
Thiazine -4- ketone；
2- [4- (neopentyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -
4- ketone；
2- [4- (cyclopentyl-methyl) (ethyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone；
2- [4- (cyclohexyl methyl) (cyclopropyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3]
Thiazine -4- ketone；
2- [3- (cyclohexyl methyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone；
2- [3- (to trifluoromethoxy benzyl) (methyl) amino piperidine -1- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone.
2. application of the compound described in claim 1 in preparation treatment tuberculosis.
3. application of the pharmaceutical composition containing compound described in claim 1 in preparation treatment tuberculosis.
4. the application of Claims 2 or 3, which is characterized in that the tuberculosis is active tuberculosis, single resistant tuberculosis, more
Resistant tuberculosis and extensive multi-drug resistance tuberculosis.
5. the application of Claims 2 or 3, which is characterized in that the tuberculosis is pulmonary tuberculosis, the outer tuberculosis of lung.
6. using compound described in claim 1 as the pharmaceutical composition of active constituent.
7. pharmaceutical composition according to claim 6, which is characterized in that the composition is selected from tablet, capsule, particle
Agent, syrup, powder-injection, injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610094025.1A CN105669664B (en) | 2016-02-19 | 2016-02-19 | Benzothiazine -4- ketone compounds containing basic nitrogen heterocyclic fragments and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610094025.1A CN105669664B (en) | 2016-02-19 | 2016-02-19 | Benzothiazine -4- ketone compounds containing basic nitrogen heterocyclic fragments and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105669664A CN105669664A (en) | 2016-06-15 |
| CN105669664B true CN105669664B (en) | 2019-05-10 |
Family
ID=56304758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610094025.1A Active CN105669664B (en) | 2016-02-19 | 2016-02-19 | Benzothiazine -4- ketone compounds containing basic nitrogen heterocyclic fragments and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105669664B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3072889A1 (en) * | 2015-03-23 | 2016-09-28 | Ecole Polytechnique Federale De Lausanne (Epfl) | 2-Homopiperazine-1-yl-4H-1,3-benzothiazine-4-one derivatives and process for the preparation of 2-(homo)piperazine 1,3-benzothiazine-4-one hydrochlorides |
| CN108456204B (en) * | 2017-02-17 | 2023-05-26 | 四川大学 | Benzothiazine derivative, and preparation method and application thereof |
| CN108530448A (en) * | 2017-03-02 | 2018-09-14 | 浙江司太立制药股份有限公司 | Benzothiazine -4- ketone compounds containing alkaline azaspiro segment and preparation method thereof |
| CN112759560B (en) * | 2021-01-14 | 2022-06-21 | 中国医学科学院医药生物技术研究所 | Benzothiazine-4-ketone compound containing N-aminopiperazine segment and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007134625A1 (en) * | 2006-05-24 | 2007-11-29 | Leibniz Institute For Natural Product Research And Infection Biology E.V. Hans-Knöll-Institut (Hki) | New benzothiazinone derivatives and their use as antibacterial agents |
| EP2468746A1 (en) * | 2010-12-23 | 2012-06-27 | The University of Queensland | Benzothiazinone compounds and their use as anti-tuberculosis agents |
| EP2570413A1 (en) * | 2011-09-15 | 2013-03-20 | The University Of Queensland | Benzothiazinone derivatives as anti-tuberculosis agents |
| CN103508980A (en) * | 2012-06-14 | 2014-01-15 | 四川大学 | Benzothiazine-4-one derivative, and preparation method and applications thereof |
-
2016
- 2016-02-19 CN CN201610094025.1A patent/CN105669664B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007134625A1 (en) * | 2006-05-24 | 2007-11-29 | Leibniz Institute For Natural Product Research And Infection Biology E.V. Hans-Knöll-Institut (Hki) | New benzothiazinone derivatives and their use as antibacterial agents |
| EP2468746A1 (en) * | 2010-12-23 | 2012-06-27 | The University of Queensland | Benzothiazinone compounds and their use as anti-tuberculosis agents |
| EP2570413A1 (en) * | 2011-09-15 | 2013-03-20 | The University Of Queensland | Benzothiazinone derivatives as anti-tuberculosis agents |
| CN103508980A (en) * | 2012-06-14 | 2014-01-15 | 四川大学 | Benzothiazine-4-one derivative, and preparation method and applications thereof |
Non-Patent Citations (2)
| Title |
|---|
| Identification of Antitubercular Benzothiazinone Compounds by Ligand-Based Design;Tomislav Karoli，等;《J. Med. Chem.》;20120823;第55卷;7940-7944和supporting information * |
| Novel Fluoroquinolone Antibacterial Agents Containing Oxime-Substituted (Aminomethyl)pyrrolidines: Synthesis and Antibacterial Activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carb;Chang Yong Hong，等;《J. Med. Chem.》;19971231;第40卷(第22期);3584-3593 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105669664A (en) | 2016-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10561666B2 (en) | Amido compounds as RORγt modulators and uses thereof | |
| CN108358917B (en) | Imidazo [1,2-a ] pyridine-3-amide compound containing basic fused ring segment and preparation method thereof | |
| CN105669664B (en) | Benzothiazine -4- ketone compounds containing basic nitrogen heterocyclic fragments and preparation method thereof | |
| CN105622596B (en) | Benzothiazine -4- ketone compounds and preparation method thereof containing alcoxyl imido grpup azacyclo- segment | |
| TW201008930A (en) | Heterocyclic compounds as factor IXa inhibitors | |
| TW200413331A (en) | Small molecule PI 3-kinase inhibitors and methods of their use | |
| US20170080011A1 (en) | Use of nadh and nmn in preparation of drugs or health-care products for treating parkinson's disease | |
| US20220040181A1 (en) | Combination therapies | |
| CN106543106B (en) | N- benzyl benzamide compounds and preparation method thereof | |
| CN101209974A (en) | Hydroxamic acids derivatives and use thereof | |
| CN108530447B (en) | Benzothiazine -4- ketone compounds and preparation method thereof containing 2,7- diaza spiro [3.5] nonane segment | |
| CN110204546A (en) | Benzothiazine -4- ketone compounds containing diazacyclo segment and preparation method thereof | |
| CN103965193B (en) | N-(benzene oxyalkyl) imidazo [1,2-a] pyridine-3-amides and preparation method thereof | |
| CN108530448A (en) | Benzothiazine -4- ketone compounds containing alkaline azaspiro segment and preparation method thereof | |
| TW200409629A (en) | 2,4-disubstituted-pyridine N-oxides useful as HIV reverse transcriptase inhibitors | |
| CN108440446A (en) | Benzothiazine -4- ketone compounds containing oximido segment and preparation method thereof | |
| CN106588916A (en) | N-(phenoxyethyl) imidazo [1,2-a] pyridine-3-amide compound and preparation method thereof | |
| CN108484601B (en) | Contain the benzothiazine -4- ketone compounds and preparation method thereof of 2,8- diaza spiro [4.5] decane segment | |
| CN110590779B (en) | 3, 10 di-p-chlorophenyl 6, 12 diazatetracubane compound, and synthetic method, application and pharmaceutical composition thereof | |
| CN108623527A (en) | DprE1 enzyme inhibitors | |
| CN104926804B (en) | One kind has compound, the preparation method and use of antitumor action | |
| CN107674014B (en) | 3, 5-dinitrobenzamide compound containing isoindoline fragment and preparation method thereof | |
| CN111494381A (en) | Application of alkenyl quinoline compound in preparation of antitumor drugs | |
| CN108976227A (en) | Benzothiazine -4- ketone compounds containing alkaline bridged ring segment and preparation method thereof | |
| CN109503631A (en) | Imidazo [1,2-a] pyridine -3- amides compound containing diazaspiracyclic segment and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |