CN110204546A - Benzothiazine -4- ketone compounds containing diazacyclo segment and preparation method thereof - Google Patents
Benzothiazine -4- ketone compounds containing diazacyclo segment and preparation method thereof Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to benzothiazine -4- ketone compounds, preparation method and medical usage shown in formula (I) and formula (II) and using it as the antitubercular pharmaceutical composition of effective component.More particularly, it relates to one kind 6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone compounds, 2- bit substituent is the heterocyclic fragments containing two nitrogen-atoms, and wherein Ar represents aromatic radical.
Description
Technical field
The invention belongs to medicinal chemistry arts, it is related to the benzo containing alkaline diazacyclo segment with anti-tubercular
Thiazine ketone compounds and preparation method thereof, and the antitubercular pharmaceutical composition containing them；More specifically, the present invention relates to
And 6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone compounds, 2- bit substituent is containing two nitrogen
The heterocyclic fragments of atom.
Background technique
Estimate according to the World Health Organization (WHO), the whole world increases tuberculosis (TB) patient 10,400,000,1,400,000 people newly within 2015
Die of TB.In addition, nearly 1/3 population in the whole world carries latent form tubercle bacillus, there is potential initiation potential.In recent years, drug resistance TB,
The disease incidence of especially multi-drug resistant TB (MDR-TB) constantly rises and the appearance of drug resistance TB (XDR-TB) extensively, it has also become the whole world
The great public health problem and social concern of concern.Traditional anti-TB drug is invalid to MDR-TB, and to latent form tuberculosis point
The effect of branch bacillus (MTB) is not strong, therefore researches and develops anti-TB new drug, realizes that the effective treatment and control to TB are imperative
(Chemical biology&drug design, 2016,87,537-550).
After the dormancy phase gloomy in more than 40 years, the research and development of anti-TB new drug are obtaining important breakthrough finally in recent years.
Shellfish is successively ratified by U.S. FDA and European Bureau of Drugs Supervision (EMA) for clinical treatment MDR-TB up to quinoline and De Lamanni.But due to
In the presence of the risk for inducing arrhythmia cordis, the two is only recommended for without the alternative adult MDR-TB's of other clinical protocols
It treats (Adv Drug Deliv Rev.2016,102,55-72).Nevertheless, multiple big drugmakers global in recent years and grinding
Study carefully unit and increase the R&D intensity of confrontation TB new drug, and it is candidates to disclose several anti-TB with different role mechanism of report
Close object.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).
Ma Kaluowa is equal to 4H- benzo [e] [1,3] thiophene for disclosing that a kind of 2- bit substituent is piperazine -1- base for 2011
The synthesis of piperazine -4- ketone compounds and anti-tubercular (CN 201180055813.5).It represents object PBTZ169 with outstanding
Wide spectrum anti-tubercular (EMBO Mol Med, 2014,6:372-383), an II clinical trial phase will be in the 2018 year end of the year
It completes.
Liu Mingliang etc. discloses the different types of benzothiazine -4- ketone containing alkaline azaspiro segment or bridged ring segment
Class compound (CN 201710121170.9, CN 201710121169.9, CN 201710121414.3,
2017104120720), terminal nitrogen atom is connected with benzyl.Subsequent correlative study discovery, although these compounds are shown
Good wide spectrum anti-tubercular and pharmacokinetic property, but because there are potential cardiac toxics (under 10 μM, to hERG K+Inhibiting rate > 90% in channel) and influence its druggability.
To overcome defect present in the above-mentioned prior art, present inventor has performed extensive research, by it is above-mentioned with
The benzyl position that azaspiro or the terminal nitrogen atom of bridged ring segment are connected introduces specific substituent group, and design has synthesized diaza ring plate
Benzothiazine -4- the ketone compounds of section, and preliminary assessment their anti-tubercular and cardiac toxic.It finally found that, no
It is same as the 6- trifluoromethyl -8- nitro-containing diazacyclo segment and its benzyl position connection specified substituent of previous literature report
4H- benzo [e] [1,3] thiazine -4- ketone compounds have unexpected compared with similar benzothiazine -4- ketone compounds
Strong anti-tubercular and weaker cardiac toxic, show good druggability.
Summary of the invention
The 6- fluoroform containing diazacyclo segment that the object of the present invention is to provide one kind to be indicated by leading to formula (I) with (II)
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone compounds,
Wherein:
M, n, o and p represent 0 or 1, and wherein m, n, o and p are identical or different；
R represents CH2CN has C1-C6 straight chain, branch or cricoid alkyl；
Ar represents phenyl, pyridyl group, naphthalene, quinolyl, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thiophene
Pheno base, and optionally, wherein 0-3 hydrogen atom is replaced by W group；
W is selected from alkyl, halogen, OCH with C1-C43、CF3、OCF3、NO2Or CN.
The present invention specifically includes following compound:
2- [2- (1- (4- Trifluoromethoxyphen-l) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- chlorphenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- bromophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- fluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (3- fluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (3,5- difluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (3,4,5- trifluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (the chloro- 4- fluorophenyl of 3-) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (the chloro- 3- fluorophenyl of 4-) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) propyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (2- methyl-1-(4- trifluoromethoxy benzaldehyde base) propyl)-2,7- diaza spiro [3.5] nonane-7- base]-6- three
Methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (2,2- dimethyl -1- (4- trifluoromethoxy benzaldehyde base) propyl) -2,7- diaza spiro [3.5] nonane -7- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) butyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- cyclopropyl -1- (4- trifluoromethoxy benzaldehyde base) methyl) -2,7- diaza spiro [3.5] nonane -7- base] -6-
Trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
3- [(7- (6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone -2- base) -2,7- diaza spiro
[3.5] nonane -2- base] -3- (4- trifluoromethoxy benzaldehyde base) propionitrile
2- [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (4- methoxyphenyl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (4- tert-butyl-phenyl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyridin-4-yl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyridin-3-yl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyridine -2- base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyrimidine -5- base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyrimidine -2-base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (5- trifluoromethoxy pyridine -2- base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- three
Methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (6- trifluoromethoxy pyridin-3-yl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- three
Methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [8- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,8- diaza spiro [4.5] decane -2- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [9- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,9- diaza spiro [5.5] hendecane -3- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,7- diaza spiro [4.4] nonane -2- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiro [3.4] octane -6- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiro [3.4] octane -2- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiroheptane -2- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [5- (1- (4- trifluoromethoxy benzaldehyde base) ethyl)-hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl] -6- trifluoro
Methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) octahydro -5H- pyrrolo- [3,4-c] pyridine -5- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [5- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) octahydro -5H- pyrrolo- [3,4-c] pyridine -2- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [3- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,7- diazacyclo [4.2.0] octane -7- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,7- diazacyclo [4.2.0] octane -3- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,6- diazacyclo [3.2.0] heptane -3- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [3- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,6- diazacyclo [3.2.0] heptane -6- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The invention further relates to the preparation methods of formula (I) and formula (II) compound, as shown in reaction scheme 1.
Reaction route 1:
In reaction route 1, m, n, o, p, R and Ar are defined as the aforementioned.
Acid binding agent is added in protonic solvent, make formula (III) compound respectively with formula (IV) compound and formula (V) chemical combination
Object prepares formula (I) compound and formula (II) compound by condensation reaction.Protonic solvent for this reaction is selected from water, alcohol
Or alcohol-water mixed solvent；The acid binding agent is selected from triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or hydrogen-oxygen
Change potassium.
Formula (III) compound as starting material is known compound in the present invention, and in the existing publication of reference
The method known can easily be made, such as CN 201180055813.5.
According to method shown in following reaction routes 2, the formula (IV) and formula (V) of another two classes starting material of the invention can be prepared
Compound.
Reaction route 2:
In reaction route 2, m, n, o, p, R and Ar are defined as the aforementioned.
Condensing agent is added in non-protonic solvent, make formula (VI) compound and formula (VII) compound respectively with formula
(VIII) condensation reaction occurs for compound, and intermediate generated is directly sloughed protecting group with trifluoroacetic acid, that is, divided without separation
Formula (IV) compound and formula (V) compound are not obtained.Non-protonic solvent for this reaction is selected from acetonitrile, acetone, dichloromethane
Alkane, chloroform, ether or hexamethylene；The condensing agent is selected from titanium tetrachloride, butyl titanate, metatitanic acid tetra isopropyl ester.
Formula (VI) compound, formula (VII) and formula (VIII) compound as starting material are known compound, and the country has
Supply of commodities.
The present invention also provides contain the resistive connection of formula as defined above (I) and/or formula (II) compound as active constituent
Core composition.The weight ratio of the compounds of this invention that pharmaceutical composition contains in the composition is 0.1~99.9%, and drug can connect
The weight ratio of the carrier received in the composition is 0.1~99.9%.Pharmaceutical composition is to be suitble to medicinal dosage form to exist.This
The pharmaceutical composition of invention can be prepared into any pharmaceutical dosage form.Preferably, medicinal preparation be tablet, sugar coated tablet,
Film coated tablet, enteric coated tablet, sustained-release tablet, capsule, hard capsule, soft capsule, Duracaps, powder.
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.
It is excellent when formula (I) and formula (II) reactive compound of the invention are used as the drug for the treatment of mycobacterium tuberculosis infection
It is selected in the amount that the first stage gives 6~14mg/kg weight.But dosage can be with sick human needs, the infection to be treated
Seriousness, 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 application of the compound shown in formula (I) in preparation treatment tuberculosis.
The present invention also provides application of the compound shown in formula (II) in preparation treatment tuberculosis.
The present invention also provides the pharmaceutical compositions containing compound shown in formula (I) and/or formula (II) to treat tuberculosis in preparation
Application in the drug of disease.Tuberculosis of the present invention include active tuberculosis, single resistant tuberculosis, more resistant tuberculosis with
And extensive multi-drug resistance tuberculosis.
Tuberculosis of the present invention includes pulmonary tuberculosis, the outer tuberculosis of lung.
As described above, the compounds of this invention is to mycobacterium tuberculosis type strain H37Rv ATCC 27294 and clinical separation strain
The external activity of MDR-MTB16833 (to rifampin and Isoniazid-resistant) is suitable with comparison medicine PBTZ169, but pharmacokinetics
Property is substantially better than PBTZ169, and cardiac toxic is then weaker than the similar patents of structure type and PBTZ169.
The compound of the present invention is for existing product, and curative effect may be more preferable in terms for the treatment of tuberculosis, and side effect is 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 [2- (1- (4- Trifluoromethoxyphen-l) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
At room temperature, 4- trifluoro is added into 2,7- azaspiro [3,5] nonane -7- carboxylic acid tert-butyl ester (226mg, 1.0mmol)
Methoxyacetophenone (204mg, 1.0mmol) and tetraisopropyl titanate (568mg, 2.0mmol), 80 DEG C of reactions are overnight.It is cooled to
Then sodium cyanoborohydride (188mg, 3.0mmol) is added into system in room temperature, 40 DEG C are reacted 2 hours.Post-processing: water is added to extract
It negates and answers, methylene chloride extracts (20mL × 3).Merge organic layer, anhydrous magnesium sulfate is dry, concentration, through silica gel column chromatography (acetic acid
Ethyl ester: petroleum ether=1:2) obtain light yellow oil (150mg).
At room temperature, the above grease (150mg) is dissolved in anhydrous methylene chloride (10mL), stirs lower dropwise addition trifluoroacetic acid
(3mL), equality of temperature stir 1 hour, are concentrated to give yellow oil.
2- methyl mercapto -6- trifluoromethyl -8- nitro-is added into dehydrated alcohol (10mL) solution of above-mentioned yellow oil
Benzothiazine -4- ketone (128mg, 0.4mmol), triethylamine (61mg, 0.6mmol), 40 DEG C are stirred 3 hours, concentration, silicagel column point
From purifying (ethyl acetate: petroleum ether=1:1), faint yellow target compound (85mg, 40%) is obtained.
1H NMR(500MHz,CDCl3) δ 9.09 (s, 1H), 8.75 (s, 1H), 7.32 (d, J=10.00Hz, 2H), 7.14
(d, J=10.00Hz, 2H), 4.04-3.78 (m, 4H), 3.34 (d, J=5.00Hz, 1H), 3.04-2.98 (m, 4H), 1.91
(brs, 4H), 1.18 (d, J=5.00Hz, 3H)；MS-ESI(m/z):589.1(M+H)+。
2. 2- of embodiment [2- (1- (4- trifluoromethyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6-
Trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- trifluoromethyl) ethyl) -2,7- diaza spiro [3.5] nonane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR (500MHz, CDCl3) δ 9.09 (s, 1H), 8.75 (s, 1H), 7.39 (d, J=10.00Hz, 2H), 7.14
(d, J=10.00Hz, 2H), 4.05-3.83 (m, 4H), 3.37 (d, J=5.00Hz, 1H), 3.05-2.99 (m, 4H), 1.93
(brs, 4H), 1.19 (d, J=5.00Hz, 3H)；MS-ESI(m/z):573.1(M+H)+。
3. 2- of embodiment [2- (1- (4- chlorphenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- chlorphenyl) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR (500MHz, CDCl3) δ 9.08 (s, 1H), 8.74 (s, 1H), 7.22 (d, J=10.00Hz, 2H), 6.96
(d, J=10.00Hz, 2H), 4.03-3.75 (m, 4H), 3.38 (d, J=5.00Hz, 1H), 3.07-3.01 (m, 4H), 1.90
(brs, 4H), 1.18 (d, J=5.00Hz, 3H)；MS-ESI(m/z):539.1(M+H)+。
4. 2- of embodiment [2- (1- (4- bromophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- bromophenyl) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.07 (s, 1H), 8.73 (s, 1H), 7.21 (d, J=10.00Hz, 2H), 6.89
(d, J=10.00Hz, 2H), 4.02-3.78 (m, 4H), 3.35 (d, J=5.00Hz, 1H), 3.03-2.99 (m, 4H), 1.91
(brs, 4H), 1.20 (d, J=5.00Hz, 3H)；MS-ESI(m/z):583.1(M+H)+。
5. 2- of embodiment [2- (1- (4- fluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- fluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.09 (s, 1H), 8.72 (s, 1H), 7.27 (t, J=10.00Hz, 2H), 6.98
(t, J=10.00Hz, 2H), 4.03-3.77 (m, 4H), 3.36 (d, J=5.00Hz, 1H), 3.07-3.01 (m, 4H), 1.91
(brs, 4H), 1.18 (d, J=5.00Hz, 3H)；MS-ESI(m/z):523.1(M+H)+。
6. 2- of embodiment [2- (1- (3- fluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (3- fluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3)δ9.09(s,1H),8.74(s,1H),7.26(m,1H),7.09-7.04(m,2H),
6.93 (t, J=10.00Hz, 1H), 4.02-3.79 (m, 4H), 3.36 (d, J=5.00Hz, 1H), 3.07-3.01 (m, 4H),
1.91 (brs, 4H), 1.18 (d, J=5.00Hz, 3H)；MS-ESI(m/z):523.1(M+H)+。
7. 2- of embodiment [2- (1- (3,5- difluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- three
Methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (3,5- difluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane and 2-
Pale yellow powder shape solid is made in methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.07 (s, 1H), 8.73 (s, 1H), 6.85 (d, J=5.00Hz, 2H), 6.68
(t, J=5.00Hz, 1H), 4.05-3.77 (m, 4H), 3.33 (d, J=5.00Hz, 1H), 3.06-3.01 (m, 4H), 1.91
(brs, 4H), 1.18 (d, J=5.00Hz, 3H)；MS-ESI(m/z):541.1(M+H)+。
8. 2- of embodiment [2- (1- (3,4,5- trifluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6-
Trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (3,4,5- trifluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.09 (s, 1H), 8.72 (s, 1H), 6.94 (t, J=10.00Hz, 2H), 4.03-
3.79 (m, 4H), 3.36 (d, J=5.00Hz, 1H), 3.05-3.01 (m, 4H), 1.93 (brs, 4H), 1.18 (d, J=
5.00Hz,3H)；MS-ESI(m/z):558.1(M+H)+。
9. 2- of embodiment [2- (1- (the chloro- 4- fluorophenyl of 3-) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6-
Trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (the chloro- 4- fluorophenyl of 3-) ethyl) -2,7- diaza spiro [3.5] nonane and 2-
Pale yellow powder shape solid is made in methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.09 (s, 1H), 8.74 (s, 1H), 6.98 (s, 1H), 6.85 (d, J=
6.00Hz, 1H), 6.63 (m, 1H), 4.02-3.78 (m, 4H), 3.31 (d, J=5.00Hz, 1H), 3.02-3.00 (m, 4H),
1.91 (brs, 4H), 1.18 (d, J=5.54Hz, 3H)；MS-ESI(m/z):557.1(M+H)+。
10. 2- of embodiment [2- (1- (the chloro- 3- fluorophenyl of 4-) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6-
Trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (the chloro- 3- fluorophenyl of 4-) ethyl) -2,7- diaza spiro [3.5] nonane and 2-
Pale yellow powder shape solid is made in methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.09 (s, 1H), 8.75 (s, 1H), 6.84 (d, J=6.00Hz, 2H), 6.66
(t, J=8.00Hz, 1H), 4.00-3.78 (m, 4H), 3.31 (d, J=5.05Hz, 1H), 3.02-3.00 (m, 4H), 1.92
(brs, 4H), 1.18 (d, J=5.54Hz, 3H)；MS-ESI(m/z):557.1(M+H)+。
11. 2- of embodiment [2- (1- (4- trifluoromethoxy benzaldehyde base) propyl) -2,7- diaza spiro [3.5] nonane -7- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- trifluoromethoxy benzaldehyde base) propyl) -2,7- diaza spiro [3.5] nonane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.06 (s, 1H), 8.73 (s, 1H), 7.21 (d, J=7.50Hz, 2H), 6.85
(t, J=8.00Hz, 2H), 4.02 (brs, 4H), 3.22 (d, J=5.00Hz, 1H), 3.02-2.98 (m, 4H), 1.92 (brs,
4H),1.75-1.73(m,2H),1.01-0.96(m,3H)；MS-ESI(m/z):603.2(M+H)+。
12. 2- of embodiment [2- (2- methyl-1-(4- trifluoromethoxy benzaldehyde base) propyl)-2,7- diaza spiro [3.5] nonane-
7- yl] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (2- methyl-1-(4- trifluoromethoxy benzaldehyde base) propyl)-2,7- diaza spiro [3.5]
Pale yellow powder is made in nonane and 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
Shape solid
1H NMR(500MHz,CDCl3) δ 9.08 (s, 1H), 8.74 (s, 1H), 7.22 (d, J=8.00Hz, 2H), 6.86
(d, J=8.00Hz, 2H), 4.01-3.77 (m, 4H), 3.12 (d, J=5.15Hz, 1H), 3.02-3.00 (m, 4H), 2.01-
1.99(m,1H),1.92(brs,4H),1.08-1.00(m,6H)；MS-ESI(m/z):617.2(M+H)+。
13. 2- of embodiment [2- (2,2- dimethyl -1- (4- trifluoromethoxy benzaldehyde base) propyl) -2,7- diaza spiro [3.5]
Nonane -7- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (2,2- dimethyl -1- (4- trifluoromethoxy benzaldehyde base) propyl) -2,7- diaza spiro
[3.5] nonane and 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone, are made faint yellow
Pulverulent solids
1H NMR(500MHz,CDCl3) δ 9.08 (s, 1H), 8.74 (s, 1H), 7.21 (d, J=7.50Hz, 2H), 6.87
(d, J=8.15Hz, 2H), 4.01-3.75 (m, 4H), 3.31-3.29 (m, 1H), 3.02-3.00 (m, 4H), 1.91-1.88 (m,
4H),1.16(s,9H)；MS-ESI(m/z):631.2(M+H)+。
14. 2- of embodiment [2- (1- (4- trifluoromethoxy benzaldehyde base) butyl) -2,7- diaza spiro [3.5] nonane -7- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- trifluoromethoxy benzaldehyde base) butyl) -2,7- diaza spiro [3.5] nonane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.08 (s, 1H), 8.74 (s, 1H), 7.21 (d, J=8.00Hz, 2H), 6.85
(t, J=8.15Hz, 2H), 4.02-3.77 (m, 4H), 3.14-3.11 (m, 1H), 3.02-3.00 (m, 4H), 1.92 (brs,
4H), 1.76-1.74 (m, 2H), 1.08-0.99 (m, 5H)；MS-ESI(m/z):617.2(M+H)+。
15. 2- of embodiment [2- (1- cyclopropyl -1- (4- trifluoromethoxy benzaldehyde base) methyl) -2,7- diaza spiro [3.5] nonyl
Alkane -7- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- cyclopropyl -1- (4- trifluoromethoxy benzaldehyde base) methyl) -2,7- diaza spiro
[3.5] nonane and 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone, are made faint yellow
Pulverulent solids
1H NMR(500MHz,CDCl3) δ 9.08 (s, 1H), 8.71 (s, 1H), 7.21 (d, J=8.05Hz, 2H), 6.87
(t, J=8.00Hz, 2H), 4.02-3.75 (m, 4H), 3.13-3.11 (m, 1H), 3.02-2.98 (m, 4H), 1.91 (brs,
4H),1.05-1.00(m,1H),0.87-0.80(m,4H)；MS-ESI(m/z):615.2(M+H)+。
16. 3- of embodiment [(7- (6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone -2- base) -2,
7- diaza spiro [3.5] nonane -2- base] -3- (4- trifluoromethoxy benzaldehyde base) propionitrile
The preparation method is the same as that of Example 1,3- (2,7- diaza spiros [3.5] nonane -2- base) -3- (4- trifluoromethoxy benzaldehyde base) third
Pale yellow powder shape is made in nitrile and 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
Solid
1H NMR(500MHz,CDCl3) δ 9.09 (s, 1H), 8.71 (s, 1H), 7.25 (d, J=7.50Hz, 2H), 6.89
(t, J=8.00Hz, 2H), 4.03-3.76 (m, 4H), 3.23-3.19 (m, 1H), 3.12-3.08 (m, 4H), 2.34 (d, J=
7.50Hz,2H),1.94(brs,4H)；MS-ESI(m/z):614.3(M+H)+。
17. 2- of embodiment [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,7- diaza spiro [3.5] nonane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.76 (s, 1H), 7.33 (d, J=7.00Hz, 2H), 7.15
(d, J=7.15Hz, 2H), 4.05 (brs, 2H), 3.99 (brs, 2H), 3.41 (d, J=5.00Hz, 1H), 2.42-2.35 (m,
4H), 1.85 (brs, 4H), 1.33 (d, J=4.50Hz, 3H)；MS-ESI(m/z):589.3(M+H)+。
18. 2- of embodiment [7- (1- (4- methoxyphenyl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6-
Trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (4- anisyl) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first
Pale yellow powder shape solid is made in sulfenyl -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.75 (s, 1H), 7.13 (d, J=8.00Hz, 2H), 6.85
(d, J=7.50Hz, 2H), 4.04 (brs, 2H), 3.98 (brs, 5H), 3.31 (d, J=5.00Hz, 1H), 2.40-2.32 (m,
4H), 1.82 (brs, 4H), 1.32 (d, J=5.00Hz, 3H)；MS-ESI(m/z):535.3(M+H)+。
19. 2- of embodiment [7- (1- (4- tert-butyl-phenyl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6-
Trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (4- tert-butyl-phenyl) ethyl) -2,7- diaza spiro [3.5] nonane and 2-
Pale yellow powder shape solid is made in methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.14 (s, 1H), 8.75 (s, 1H), 7.12 (d, J=8.00Hz, 2H), 6.81
(d, J=8.00Hz, 2H), 4.01 (brs, 2H), 3.94 (brs, 2H), 3.31-3.28 (m, 1H), 2.40-2.32 (m, 4H),
1.82(brs,4H),1.32-1.30(m,3H),1.00(s,9H)；MS-ESI(m/z):535.3(M+H)+。
20. 2- of embodiment [7- (1- (pyridin-4-yl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoro
Methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (pyridin-4-yl) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.76 (s, 1H), 8.53 (d, J=7.50Hz, 2H), 7.35
(d, J=7.50Hz, 2H), 4.05-3.91 (m, 4H), 3.42 (d, J=5.00Hz, 1H), 2.41-2.30 (m, 4H), 1.85
(brs, 4H), 1.33 (d, J=5.00Hz, 3H)；MS-ESI(m/z):506.3(M+H)+。
21. 2- of embodiment [7- (1- (pyridin-3-yl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoro
Methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (pyridin-3-yl) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.76 (s, 1H), 8.52 (s, 1H), 8.36 (d, J=
7.50Hz, 1H), 7.32-7.30 (m, 2H), 4.02 (brs, 4H), 3.39 (d, J=5.00Hz, 1H), 2.41-2.31 (m, 4H),
1.85 (brs, 4H), 1.33 (d, J=5.15Hz, 3H)；MS-ESI(m/z):506.3(M+H)+。
22. 2- of embodiment [7- (1- (pyridine -2- base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoro
Methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (pyridine -2- base) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR (500MHz, CDCl3) δ 9.15 (s, 1H), 8.76 (s, 1H), 8.50 (J=7.50Hz, 1H), 7.66 (d, J
=7.50Hz, 1H), 7.32-7.28 (m, 2H), 4.02 (brs, 4H), 3.52 (d, J=5.00Hz, 1H), 2.41-2.30 (m,
4H), 1.85 (brs, 4H), 1.33 (d, J=5.15Hz, 3H)；MS-ESI(m/z):506.3(M+H)+。
23. 2- of embodiment [7- (1- (pyrimidine -5- base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoro
Methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (pyrimidine -5- base) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3)δ9.15(s,1H),9.11(s,1H),8.75(s,1H),8.70(s,2H),4.02
(brs, 4H), 3.52 (d, J=5.00Hz, 1H), 2.41-2.30 (m, 4H), 1.85 (brs, 4H), 1.33 (d, J=5.15Hz,
3H)；MS-ESI(m/z):507.3(M+H)+。
24. 2- of embodiment [7- (1- (pyrimidine -2-base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoro
Methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (pyrimidine -2-base) ethyl) -2,7- diaza spiro [3.5] nonane and 2- first sulphur
Pale yellow powder shape solid is made in base -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.75 (s, 1H), 8.71 (d, J=8.00Hz, 2H), 7.92-
7.89 (m, 1H), 4.01 (brs, 4H), 3.50 (d, J=5.15Hz, 1H), 2.41-2.30 (m, 4H), 1.82 (brs, 4H),
1.34 (d, J=5.15Hz, 3H)；MS-ESI(m/z):507.3(M+H)+。
25. 2- of embodiment [7- (1- (5- trifluoromethoxy pyridine -2- base) ethyl) -2,7- diaza spiro [3.5] nonane -
2- yl] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (5- trifluoromethoxy pyridine -2- base) ethyl) -2,7- diaza spiro [3.5]
Pale yellow powder is made in nonane and 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
Shape solid
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.76 (s, 1H), 8.30 (s, 1H), 8.00 (d, J=
8.00Hz, 1H), 7.87 (d, J=8.00Hz, 1H), 4.01-3.89 (m, 4H), 3.51 (d, J=5.15Hz, 1H), 2.41-
2.30 (m, 4H), 1.81 (brs, 4H), 1.34 (d, J=5.15Hz, 3H)；MS-ESI(m/z):590.3(M+H)+。
26. 2- of embodiment [7- (1- (6- trifluoromethoxy pyridin-3-yl) ethyl) -2,7- diaza spiro [3.5] nonane -
2- yl] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (6- trifluoromethoxy pyridin-3-yl) ethyl) -2,7- diaza spiro [3.5]
Pale yellow powder is made in nonane and 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
Shape solid
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.76 (s, 1H), 7.57 (d, J=8.15Hz, 1H), 7.47
(s, 1H), 7.34 (d, J=8.00Hz, 1H), 4.01-3.89 (m, 4H), 3.51 (d, J=5.15Hz, 1H), 2.41-2.30 (m,
4H), 1.82 (brs, 4H), 1.33 (d, J=5.15Hz, 3H)；MS-ESI(m/z):590.3(M+H)+。
27. 2- of embodiment [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,8- diaza spiro [4.5] decane -8- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,8- diaza spiro [4.5] decane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.07 (s, 1H), 8.71 (s, 1H), 7.23 (d, J=8.00Hz, 2H), 6.75
(d, J=7.50Hz, 2H), 4.03-3.91 (m, 4H), 3.42 (d, J=5.00Hz, 1H), 2.31-2.26 (m, 2H), 2.25 (s,
2H), 1.65-1.63 (m, 2H), 1.13 (d, J=5.00Hz, 3H)；MS-ESI(m/z):506.3(M+H)+。
28. 2- of embodiment [8- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,8- diaza spiro [4.5] decane -2- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,8- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,8- diaza spiro [4.5] decane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.10 (s, 1H), 8.75 (s, 1H), 7.22 (d, J=8.00Hz, 2H), 6.73
(d, J=8.00Hz, 2H), 3.93-3.91 (m, 4H), 3.52 (d, J=5.00Hz, 1H), 2.51-2.56 (m, 2H), 2.45 (s,
2H), 1.67-1.63 (m, 2H), 1.13 (d, J=5.10Hz, 3H)；MS-ESI(m/z):506.3(M+H)+。
29. 2- of embodiment [9- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,9- diaza spiro [5.5] hendecane -3-
Base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,9- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,9- diaza spiro [5.5] hendecane
With 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone, it is solid that pale yellow powder shape is made
Body
1H NMR(500MHz,CDCl3) δ 9.10 (s, 1H), 8.70 (s, 1H), 7.21 (d, J=8.00Hz, 2H), 6.72
(d, J=8.00Hz, 2H), 4.03-3.99 (m, 4H), 3.92-3.90 (m, 4H), 3.51 (d, J=5.00Hz, 1H), 1.87-
1.63 (m, 8H), 1.13 (d, J=5.10Hz, 3H)；MS-ESI(m/z):617.3(M+H)+。
30. 2- of embodiment [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,7- diaza spiro [4.4] nonane -2- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,7- diaza spiro [4.4] nonane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.13 (s, 1H), 8.71 (s, 1H), 7.21 (d, J=8.15Hz, 2H), 6.73
(d, J=8.15Hz, 2H), 3.97 (brs, 2H), 3.88-3.82 (m, 2H), 3.81 (d, J=5.15Hz, 1H), 3.32 (brs,
2H), 3.27-3.22 (m, 2H), 1.87-1.63 (m, 4H), 1.12 (d, J=5.10Hz, 3H)；MS-ESI(m/z):589.3(M+
H)+。
31. 2- of embodiment [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiro [3.4] octane -6- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiro [3.4] octane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.14 (s, 1H), 8.71 (s, 1H), 7.20 (d, J=8.15Hz, 2H), 6.74
(d, J=8.15Hz, 2H), 3.96 (brs, 2H), 3.87-3.84 (m, 2H), 3.81 (d, J=5.15Hz, 1H), 3.25-3.22
(m, 4H), 1.87-1.83 (m, 2H), 1.12 (d, J=5.10Hz, 3H)；MS-ESI(m/z):575.3(M+H)+。
32. 2- of embodiment [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiro [3.4] octane -2- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiro [3.4] octane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.13 (s, 1H), 8.73 (s, 1H), 7.21 (d, J=8.00Hz, 2H), 6.74
(d, J=8.15Hz, 2H), 3.81 (brs, 4H), 3.71 (d, J=5.15Hz, 1H), 3.16 (brs, 2H), 3.07-3.05 (m,
2H), 1.77-1.74 (m, 2H), 1.12 (d, J=5.10Hz, 3H)；MS-ESI(m/z):575.3(M+H)+。
33. 2- of embodiment [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiroheptane -2- base] -
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiroheptane and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.74 (s, 1H), 7.21 (d, J=8.00Hz, 2H), 6.76
(d, J=8.00Hz, 2H), 3.81 (brs, 4H), 3.51 (d, J=5.15Hz, 1H), 3.16 (brs, 4H), 1.13 (d, J=
5.10Hz,3H)；MS-ESI(m/z):561.3(M+H)+。
34. 2- of embodiment [5- (1- (4- trifluoromethoxy benzaldehyde base) ethyl)-hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H) -
Base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl)-octahydro pyrrolo- [3,4-c] pyrroles and
Pale yellow powder shape solid is made in 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
1H NMR(500MHz,CDCl3) δ 9.20 (s, 1H), 8.81 (s, 1H), 7.58 (d, J=8.00Hz, 2H), 7.45
(d, J=8.00Hz, 2H), 4.28-4.19 (m, 1H), 4.06-3.55 (m, 3H), 3.32 (brs, 1H), 3.16-3.10 (m,
1H), 3.05-2.90 (m, 1H), 2.91-2.80 (m, 1H), 2.60-2.50 (m, 3H), 1.55 (d, J=5.10Hz, 3H)；MS-
ESI(m/z):575.2(M+H)+。
35. 2- of embodiment [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) octahydro -5H- pyrrolo- [3,4-c] pyridine -5-
Base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) octahydro -1-H- pyrrolo- [3,4-c] pyrrole
Pale yellow powder shape is made in pyridine and 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
Solid
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.51 (s, 1H), 7.52 (d, J=8.00Hz, 2H), 7.40
(d, J=8.00Hz, 2H), 4.21-4.07 (m, 5H), 3.66-3.59 (m, 4H), 1.60-1.52 (m, 4H), 1.35 (d, J=
5.10Hz,3H)；MS-ESI(m/z):589.2(M+H)+。
36. 2- of embodiment [5- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) octahydro -5H- pyrrolo- [3,4-c] pyridine -2-
Base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,5- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) octahydro -1-H- pyrrolo- [3,4-c] pyrrole
Pale yellow powder shape is made in pyridine and 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone
Solid
1H NMR(500MHz,CDCl3) δ 9.14 (s, 1H), 8.51 (s, 1H), 7.52 (d, J=8.15Hz, 2H), 7.40
(d, J=8.00Hz, 2H), 4.11-4.07 (m, 1H), 3.26-3.19 (m, 4H), 2.89-2.81 (m, 4H), 1.50-1.42 (m,
4H), 1.32 (d, J=5.00Hz, 3H)；MS-ESI(m/z):589.2(M+H)+。
37. 2- of embodiment [3- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,7- diazacyclo [4.2.0] octane -7-
Base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,7- diazacyclo [4.2.0] octane
With 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone, it is solid that pale yellow powder shape is made
Body
1H NMR(500MHz,CDCl3) δ 9.16 (s, 1H), 8.50 (s, 1H), 7.50 (d, J=7.50Hz, 2H), 7.36
(d, J=7.50Hz, 2H), 4.11-4.07 (m, 1H), 3.76-3.69 (m, 3H), 2.99-2.88 (m, 5H), 1.60-1.52 (m,
2H), 1.31 (d, J=5.50Hz, 3H)；MS-ESI(m/z):574.2(M+H)+。
38. 2- of embodiment [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,7- diazacyclo [4.2.0] octane -3-
Base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,3- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,7- diazacyclo [4.2.0] octane
With 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone, it is solid that pale yellow powder shape is made
Body
1H NMR(500MHz,CDCl3) δ 9.16 (s, 1H), 8.50 (s, 1H), 7.52 (d, J=7.50Hz, 2H), 7.38
(d, J=7.00Hz, 2H), 4.11-4.07 (m, 1H), 3.80-3.69 (m, 4H), 2.99-2.91 (m, 3H), 1.71-1.52 (m,
3H), 1.31 (d, J=5.50Hz, 3H)；MS-ESI(m/z):574.2(M+H)+。
39. 2- of embodiment [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,6- diazacyclo [3.2.0] heptane -3-
Base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,6- diazacyclo [3.2.0] heptane
With 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone, it is solid that pale yellow powder shape is made
Body
1H NMR(500MHz,CDCl3) δ 9.15 (s, 1H), 8.51 (s, 1H), 7.51 (d, J=7.50Hz, 2H), 7.38
(d, J=7.00Hz, 2H), 4.13-4.10 (m, 1H), 3.80-3.77 (m, 2H), 2.98-2.91 (m, 5H), 2.01-1.92 (m,
1H), 1.29 (d, J=5.50Hz, 3H)；MS-ESI(m/z):560.2(M+H)+。
40. 2- of embodiment [3- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,6- diazacyclo [3.2.0] heptane -6-
Base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1,3- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,6- diazacyclo [3.2.0] heptane
With 2- methyl mercapto -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- reactive ketone, it is solid that pale yellow powder shape is made
Body
1H NMR (500MHz, CDCl3) δ 9.15 (s, 1H), 8.52 (s, 1H), 7.55 (d, J=8.00Hz, 2H), 7.40
(d, J=7.50Hz, 2H), 4.14-4.11 (m, 1H), 3.80-3.78 (m, 3H), 2.98-2.91 (m, 4H), 2.05-2.02 (m,
1H), 1.26 (d, J=5.50Hz, 3H)；MS-ESI(m/z):560.2(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
The minimal inhibitory concentration of ATCC 27294 and clinical separation strain MDR-MTB 16833 (to rifampin and Isoniazid-resistant)
(MIC, μ g/mL) is come what is indicated.In this experiment, with similar benzothiazine -4- ketone candidate compound PBTZ169 and a line
Anti-tubercular drug isoniazid and rifampin compare medicine.Minimal inhibitory concentration measures as follows: (tulase is fast for sterile 48 orifice plate
The fast dedicated microtest plate of susceptibility), by drug sensitive test design requirement, each hole is separately added into 2 times of concentration cultures (improvement Michaelis
7H9 fluid nutrient medium) diluted drug.The first solution of debita spissitudo is made in each compound, is diluted to respectively with culture medium (2 ×)
The every 100 μ L of hole of 48 orifice plates, the final concentration of investigational agent is added in two times of concentration of compound used therefor, each 10 gradients of every kind of compound
Respectively 8,4,2 ... 0.015 μ g/mL.Type strain H37Rv ATCC 27294 and clinical separation strain MDR-MTB 20161, often
Hole is inoculated with 100 μ l, and every hole bacterium amount is 4 × 10-3mg.Every plate be all provided with 2 without antimicrobial growth Positive control wells and two with
The growth negative control hole of distilled water substitutive medium, surrounding is sealed with adhesive tape after 48 orifice plates are covered, and is placed in wet box 37
DEG C be incubated for.Growth positive control wells and negative growth control wells are observed after 3rd day, when observing that the two has clear difference, to each
The quantity and form of a test hole bacterial growth are observed, and are determined inhibition or drug resistance and are recorded as a result, observing note again after the 7th day
Record is once confirmed.The smallest concentration of contained drug is minimal inhibitory concentration (MIC) in the control wells of asepsis growth.Measurement
As a 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-MTB16833 (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, acute toxicity has been carried out to embodiment 1,2,8 and compound
Experiment awards male mice for the solution of the two compounds containing various concentration is oral, and dosage is 0.1ml/10g weight, and 7 days
Count dead mouse amount respectively afterwards, and the median lethal dose (LD of each compound is calculated with Bliss program50).The results are shown in Table 2.
The Mouse oral acute toxicity of 2 the compounds of this invention of table
| Experimental compound | LD50(mg/kg) |
| Embodiment 1 | >2000 |
| Embodiment 2 | >2000 |
| Embodiment 8 | >2000 |
| Embodiment 10 | >2000 |
The experimental results showed that these toxicity of compound are very low, it is very suitable to medicinal.
Internal pharmacokinetic trial
For the internal pharmacokinetic trial for measuring the compounds of this invention, is carried out to 2 compound of embodiment internal medicine generation
Dynamic test, 2 compound of embodiment and PBTZ169 oral administration gavage are awarded ICR female mice, and (every group 3, dosage is
25mg/kg weight), it takes blood (0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, for 24 hours), uses in 8 time point eye sockets respectively after administration
WinNonlin V6.2.1. software calculates area (AUC under the drug-time curve of each compound0-∞), blood Cmax (Cmax), reach peak
Time (Tmax) and half-life period (T1/2).The results are shown in Table 3.
Pharmacokinetics in the Mice Body of 3 embodiment of table, 2 compound
| PK | Embodiment 2 | PBTZ169 |
| T1/2(h) | 5.12±0.84 | 2.78±1.85 |
| Tmax(h) | 0.917±0.95 | 0.25±0 |
| Cmax(ng·mL-1) | 4189±611 | 912±156 |
| AUC0-∞(h·ng·mL-1) | 18358±5749 | 1675±711 |
| MRT(h) | 4.82±0.35 | 3.17±1.42 |
The experimental results showed that the main internal pharmacokinetic parameter of 2 compound of embodiment is all larger than PBTZ169.With
PBTZ169 is compared, the half-life period longer (T of 2 compound of embodiment1/2: 5.12h), blood Cmax (Cmax: 4189ngmL-1) and
Area (AUC under drug-time curve0-∞: 18358hngmL-1) bigger.The blood of 2 compound of embodiment is prompted to absorb bigger, and
Dosage rate is less, i.e., its druggability may be more preferable.Cardiotoxicity test
For the cardiac toxic for measuring the compounds of this invention, the heart has been carried out to 2 compound of embodiment and 34 compound of embodiment
Dirty toxicity test.2 compound of embodiment and embodiment compound 34 are dissolved in DMSO, inhale broken formula patch clamp technique using full cell
HERG (IKr) detection is carried out to HEK293 cell.Data analysis is carried out with pCLAMP10.5 software, chooses electricity after compound is added
Stream is in 3-5 sweep of stable state, calculates peak average value, the amplitude after being suppressed as electric current.Untested compound is to HERG
The inhibiting rate of electric current is calculated according to following equation: % inhibiting rate={ 1- (electric current residue amplitude)/(control current amplitude) }
X100, as a result as follows:
Table 4, cardiotoxicity test
| Experimental compound | HERG (inhibiting rate) * |
| Embodiment 2 | 30.6 ± 1.6% |
| Embodiment 34 | 39.7 ± 2.1% |
| Compound A** | 94.6 ± 2.5% |
| Compound B*** | 95.7 ± 1.3% |
| PBTZ169 | 41.6 ± 5.3% |
* to hERG K under 10 μM+Channel inhibiting rate；* compound A is that the embodiment 9 in CN201710121414.3 is changed
Close object (2- [9- (4- trifluoromethyl benzyl) -3,9- diaza spiro [5.5] hendecane -3- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone)；* * compound B is the 6 compound (2- of embodiment in CN 201710121169.9
[2- (4- luorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiophene
Piperazine -4- ketone)
The experimental results showed that 2 compound of embodiment and 34 compound of embodiment are under 10 μM to hERG K+Channel inhibiting rate
(respectively 30.6 ± 1.6% and 39.7 ± 2.1%) be significantly less than compound A (94.6 ± 2.5%) and compound B (95.7 ±
1.3%), (41.6 ± 5.3%) even less than PBTZ169.Prompt the potential cardiac toxic of this kind of compound very weak.
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
7 compound 100g of Example, is added appropriate dextrin, Steviosin, dry granulation, whole grain, packing to get.
4 injection of embodiment
8 compound 150g of Example is dissolved in water, and another sodium chloride, ethyl-para-hydroxybenzoate add hot water dissolving, mixes,
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
10 compound 150g of Example is dissolved in water, and separately plus mannitol 500g adds hot water dissolving, mixes, and water for injection is dilute
It releases to 5000ml, is filtered with hollow-fibre membrane, filling, sterilizing is lyophilized up to freeze-dried powder.
6 dripping pill of embodiment
17 compound 20g of Example 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 (10)
1. benzothiazine -4- ketone compounds, which is characterized in that shown in the structure of the compound such as formula (I), formula (II),
Wherein:
M, n, o and p represent 0 or 1, and wherein m, n, o and p are identical or different；
R represents CH2CN has C1-C6 straight chain, branch or cricoid alkyl；
Ar represents phenyl, pyridyl group, naphthalene, quinolyl, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thienyl,
And optionally, wherein 0-3 hydrogen atom is replaced by W group；
W is selected from alkyl, halogen, OCH with C1-C43、CF3、OCF3、NO2Or CN.
2. compound according to claim 1, which is characterized in that the compound are as follows:
2- [2- (1- (4- Trifluoromethoxyphen-l) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- chlorphenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- bromophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- fluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (3- fluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (3,5- difluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (3,4,5- trifluorophenyl) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (the chloro- 4- fluorophenyl of 3-) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (the chloro- 3- fluorophenyl of 4-) ethyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) propyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (2- methyl-1-(4- trifluoromethoxy benzaldehyde base) propyl)-2,7- diaza spiro [3.5] nonane-7- base]-6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (2,2- dimethyl -1- (4- trifluoromethoxy benzaldehyde base) propyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- three
Methyl fluoride -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) butyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- cyclopropyl -1- (4- trifluoromethoxy benzaldehyde base) methyl) -2,7- diaza spiro [3.5] nonane -7- base] -6- trifluoro
Methyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
3- [(7- (6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone -2- base) -2,7- diaza spiro [3.5]
Nonane -2- base] -3- (4- trifluoromethoxy benzaldehyde base) propionitrile
2- [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (4- methoxyphenyl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (4- tert-butyl-phenyl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyridin-4-yl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyridin-3-yl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyridine -2- base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyrimidine -5- base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (pyrimidine -2-base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (5- trifluoromethoxy pyridine -2- base) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (6- trifluoromethoxy pyridin-3-yl) ethyl) -2,7- diaza spiro [3.5] nonane -2- base] -6- fluoroform
Base -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [8- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,8- diaza spiro [4.5] decane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [9- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,9- diaza spiro [5.5] hendecane -3- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,7- diaza spiro [4.4] nonane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiro [3.4] octane -6- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiro [3.4] octane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -2,6- diaza spiroheptane -2- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
2- [5- (1- (4- trifluoromethoxy benzaldehyde base) ethyl)-hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [2- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) octahydro -5H- pyrrolo- [3,4-c] pyridine -5- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [5- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) octahydro -5H- pyrrolo- [3,4-c] pyridine -2- base] -6- trifluoromethyl -
8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [3- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,7- diazacyclo [4.2.0] octane -7- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [7- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,7- diazacyclo [4.2.0] octane -3- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [6- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,6- diazacyclo [3.2.0] heptane -3- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
2- [3- (1- (4- trifluoromethoxy benzaldehyde base) ethyl) -3,6- diazacyclo [3.2.0] heptane -6- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone.
3. a kind of method for preparing compound of any of claims 1 or 2, which is characterized in that it includes the following steps:
By formula (II I) compound and formula (IV) compound or formula (V) compound, in the presence of protonic solvent and acid is tied up in addition
Agent meets needs with excessive formula (III) compound, at -5 DEG C~60 DEG C, with or without be stirred to react 0.5 under pressure condition~
10 hours to get formula (I) compound or formula (II) compound,
Wherein:
M, the definition of n, o, p, R and Ar are the same as claim 1.
4. the preparation method of compound according to claim 3, which is characterized in that the protonic solvent is selected from water, alcohol
Or alcohol-water mixed solvent；The acid binding agent is selected from triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or hydrogen-oxygen
Change potassium.
5. application of the compound shown in formula (I) as claimed in claim 1 or 2 in preparation treatment tuberculosis.
6. application of the compound shown in formula (II) as claimed in claim 1 or 2 in preparation treatment tuberculosis.
7. the answering in preparation treatment tuberculosis of the pharmaceutical composition containing compound shown in formula (I) and/or formula (II)
With.
8. the application of claim 6 or 7, which is characterized in that the tuberculosis include active tuberculosis, single resistant tuberculosis,
More resistant tuberculosis and extensive multi-drug resistance tuberculosis, wherein the tuberculosis includes pulmonary tuberculosis, the outer tuberculosis of lung.
9. using compound shown in formula (I) and/or formula (II) as the pharmaceutical composition of active constituent.
10. pharmaceutical composition according to claim 9, which is characterized in that the pharmaceutical composition is prepared into any pharmaceutically acceptable
Dosage form, preferred dosage form is selected from: tablet, capsule, granule, syrup, powder-injection, injection.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409294A (en) * | 2020-04-08 | 2021-02-26 | 苏州大学 | Benzothiazinone derivative, preparation method thereof and application of benzothiazinone derivative as antituberculosis drug |
| WO2023065182A1 (en) * | 2021-10-20 | 2023-04-27 | 苏州大学 | Benzothiazinone derivative based on alkynyl linking arm, preparation method therefor, and use thereof |
| RU2806097C1 (en) * | 2023-03-20 | 2023-10-26 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | ANTITUBERCULOSIS AGENT BASED ON 4'-HYDROXY-1'-(2-HYDROXYPHENYL)-3'-ACYL-SPIRO[BENZO[b][1,4]THIAZINE-2,2'-PYRROLE]-3,5'(1 'H,4H)-DIONES |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102014012546A1 (en) * | 2014-09-26 | 2016-03-31 | Martin-Luther-Universität Halle-Wittenberg | Antimycobacterially active substances, process for their preparation and their use |
| CN108484601A (en) * | 2017-03-02 | 2018-09-04 | 浙江司太立制药股份有限公司 | Benzothiazine -4- ketone compounds and preparation method thereof containing 2,8- diaza spiros [4.5] decane segment |
| 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 |
| CN108530447A (en) * | 2017-03-02 | 2018-09-14 | 浙江司太立制药股份有限公司 | Benzothiazine -4- ketone compounds and preparation method thereof containing 2,7- diaza spiros [3.5] nonane segment |
| CN108976227A (en) * | 2017-06-02 | 2018-12-11 | 浙江司太立制药股份有限公司 | Benzothiazine -4- ketone compounds containing alkaline bridged ring segment and preparation method thereof |
-
2019
- 2019-06-14 CN CN201910512836.2A patent/CN110204546A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102014012546A1 (en) * | 2014-09-26 | 2016-03-31 | Martin-Luther-Universität Halle-Wittenberg | Antimycobacterially active substances, process for their preparation and their use |
| CN108484601A (en) * | 2017-03-02 | 2018-09-04 | 浙江司太立制药股份有限公司 | Benzothiazine -4- ketone compounds and preparation method thereof containing 2,8- diaza spiros [4.5] decane segment |
| 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 |
| CN108530447A (en) * | 2017-03-02 | 2018-09-14 | 浙江司太立制药股份有限公司 | Benzothiazine -4- ketone compounds and preparation method thereof containing 2,7- diaza spiros [3.5] nonane segment |
| CN108976227A (en) * | 2017-06-02 | 2018-12-11 | 浙江司太立制药股份有限公司 | Benzothiazine -4- ketone compounds containing alkaline bridged ring segment and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409294A (en) * | 2020-04-08 | 2021-02-26 | 苏州大学 | Benzothiazinone derivative, preparation method thereof and application of benzothiazinone derivative as antituberculosis drug |
| WO2021203812A1 (en) * | 2020-04-08 | 2021-10-14 | 苏州大学 | Benzothiazinone derivative, preparation method therefor and use thereof as anti-tuberculosis drug |
| WO2023065182A1 (en) * | 2021-10-20 | 2023-04-27 | 苏州大学 | Benzothiazinone derivative based on alkynyl linking arm, preparation method therefor, and use thereof |
| RU2806097C1 (en) * | 2023-03-20 | 2023-10-26 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | ANTITUBERCULOSIS AGENT BASED ON 4'-HYDROXY-1'-(2-HYDROXYPHENYL)-3'-ACYL-SPIRO[BENZO[b][1,4]THIAZINE-2,2'-PYRROLE]-3,5'(1 'H,4H)-DIONES |
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