CN108484601B - Contain the benzothiazine -4- ketone compounds and preparation method thereof of 2,8- diaza spiro [4.5] decane segment - Google Patents
Contain the benzothiazine -4- ketone compounds and preparation method thereof of 2,8- diaza spiro [4.5] decane segment Download PDFInfo
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Abstract
The present invention relates to contain 2, benzothiazine -4- the ketone compounds and preparation method thereof of 8- diaza spiro [4.5] decane segment, specifically, 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 2,8- diaza spiro [4.5] decane -8- base, in which: Z represents alkane (1-6 carbon atom) oxygen carbonyl, carbobenzoxy and benzyloxycarbonyl group；Alternatively, Z represents phenyl, pyridyl group, naphthalene, quinolyl, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thienyl, and optionally, the hydrogen atom of any position of these groups can be replaced by R group；R is selected from the alkyl with 1-4 carbon atom, the alkoxy with 1-3 carbon atom, halogen ,-CF3、‑OCF3、‑NO2Or-CN.
Description
Technical field
The invention belongs to medicinal chemistry arts, be related to having anti-tubercular contains alkalinity 2,8- diaza spiro [4.5]
Benzothiazine -4- ketone compounds of decane segment and preparation method thereof, and contain their antitubercular pharmaceutical composition；More
Specifically, the present invention relates to 6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone compounds, 2-
Substituent group is 2,8- diaza spiro [4.5] decane segment.
Background technique
In recent years, the disease incidence of tuberculosis (TB), especially multi-drug resistant TB (MDR-TB) constantly rise and extensive drug resistance
The appearance of TB (XDR-TB), it has also become the great public health problem and social concern of global concern.According to the World Health Organization
(WHO) estimate, the newly-increased TB patient 10,400,000 in the whole world in 2015,1,400,000 people die of TB.In addition, nearly 1/3 population in the whole world is carried and is dived
State tubercle bacillus is lied prostrate, there is potential initiation potential.Traditional anti-TB drug, such as streptomysin, isoniazid, rifampin, ethamine fourth
The drug combinations such as pure and mild pyrazinamide can make 85% or more first control lunger's recovery from illness, but (be greater than 6 there are treatment cycle is long
A month) and the disadvantage invalid to MDR-TB, while it is not strong to the effect of latent form mycobacterium tuberculosis (MTB), therefore research and develop anti-
TB new drug realizes that effective treatment to TB and control are extremely urgent (Adv Drug Deliv Rev.2016,102,55-72).
Shellfish with completely new mechanism of action is that U.S. FDA approval (is used over nearly more than 40 years up to quinoline (ATP synthetase inhibitors)
In treatment MDR-TB) the 1st anti-TB new drug.It is inspired by this, multiple big drugmakers global in recent years and research unit increase
The R&D intensity of confrontation TB new drug, and several anti-TB candidate compounds with different role mechanism of report are disclosed.These
Candidate compound is at present or in clinical experimental stage or in the preclinical study stage.
Switzerland scientist Ma Kaluowa, which is equal to, discloses a kind of 2- bit substituent for 2007 as 4,4- dialkoxy piperidines -1-
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).
The research team further disclosed the 4H- benzo [e] that a kind of 2- bit substituent is piperazine -1- base in 2011
[1,3] synthesis of thiazine -4- ketone compounds and anti-tubercular (CN 201180055813.5).It is same that it represents object PBTZ169
Sample has an external wide spectrum anti-tubercular, activity in vivo be significantly stronger than BTZ043 (EMBOMol Med, 2014,6:372-
383).As second generation benzothiazine -4- ketone treating tuberculosis candidate, PBTZ169 is currently in clinical I phase conceptual phase.
Present inventor has performed extensive research, design has synthesized the 2- benzos containing various alkaline azaspiro segments
Thiazine ketone compounds, and determine their anti-tubercular.It finally found that, 2- bit substituent of the present invention is 2,8- diaza
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone compounds of spiral shell [4.5] decane -8- base, which have, to be expected
Less than strong anti-tubercular, with similar benzothiazine -4- ketone candidate compound PBTZ169 and a different cigarette of line anti-tubercular drug
Hydrazine is compared with rifampin, has more superior anti-tubercular.
Summary of the invention
The object of the present invention is to provide one kind by leading to that formula (I) indicates containing 2,8- diaza spiro [4.5] decane segment
6- trifluoromethyl -8- nitro -4H- benzo [e] [1,3] thiazine -4- ketone compounds,
Wherein:
Z represents alkane (1-6 carbon atom) oxygen carbonyl, carbobenzoxy and benzyloxycarbonyl group；Alternatively, Z represent phenyl, pyridyl group,
Naphthalene, quinolyl, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thienyl, and optionally, these groups
The hydrogen atom of any position can be replaced by R group；
R is selected from the alkyl with 1-4 carbon atom, the alkoxy with 1-3 carbon atom, halogen ,-CF3、-OCF3、-
NO2Or-CN.
Preferably, compound shown in formula (I) of the present invention, in which:
Z is represented: methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, butoxy carbonyl, carbobenzoxy, benzyloxycarbonyl group；Alternatively, Z generation
Table phenyl, pyridyl group, pyrimidine radicals and optionally, the hydrogen atom of any position of these groups can be replaced by R group；
The R group is selected from: methyl, ethyl, propyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine ,-CF3、-OCF3、-NO2Or-
CN。
It is furthermore preferred that compound shown in formula (I) of the present invention, in which:
Z is represented: carbethoxyl group, tertbutyloxycarbonyl, carbobenzoxy, benzyloxycarbonyl group, benzyl, fluorophenyl, chlorphenyl, bromobenzene
Base, 4- trifluoromethyl, 4- Trifluoromethoxyphen-l, 4- cyano-phenyl), 4- nitrobenzophenone, 3- fluorophenyl, 3- chlorphenyl,
3- bromophenyl, 3- trifluoromethyl, 3- Trifluoromethoxyphen-l, 3- cyano-phenyl, 2,4 difluorobenzene base, 2,6- difluorobenzene
The fluoro- 3- chlorphenyl of base, 3,4- difluorophenyl, 3,5- difluorophenyl, 2,4 dichloro benzene base, 3,4- dichlorophenyl, 2-, the fluoro- 4- of 2-
The fluoro- 4- bromophenyl of chlorphenyl, 2-, the fluoro- 4- chlorphenyl of 3-, the chloro- 4- fluorophenyl of 2-, the bromo- 4- fluorophenyl of 2-, the chloro- 4- fluorophenyl of 3-,
The chloro- 3- trifluoromethyl of 4-, the fluoro- 4- trifluoromethyl of 3-, the bromo- 4- trifluoromethyl of 3-, the fluoro- 4- cyano-phenyl of 3-,
It is the bromo- 4- nitrobenzophenone of 3-, the fluoro- 5- aminomethyl phenyl of 2-, pyridine -2- ylmethyl, pyridin-3-yl methyl, pyridin-4-yl methyl, phonetic
Pyridine -2- ylmethyl.
Most preferably, compound shown in formula (I) of the present invention, in which:
Z is represented: the fluoro- 4- chlorine of carbethoxyl group, benzyloxycarbonyl group, chlorphenyl, 4- trifluoromethyl, 2,6- difluorophenyl, 3-
The chloro- 3- trifluoromethyl of phenyl, 4-.
The specific compound of the present invention are as follows:
2- (2- ethoxycarbonylmethyl group -2,8- diaza spiro [4.5] decane -8- base) -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone；
2- (2- tert-Butoxycarbonylmethyl -2,8- diaza spiro [4.5] decane -8- base) -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone；
2- (2- carbobenzoxy methyl -2,8- diaza spiro [4.5] decane -8- base) -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone；
2- (2- benzyloxycarbonyl-methyl -2,8- diaza spiro [4.5] decane -8- base) -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone；
2- (2- benzyl -2,8- diaza spiro [4.5] decane -8- base) -6- trifluoromethyl -8- nitro -4H- benzo [e] [1,
3] thiazine -4- ketone；
2- [2- (4- luorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone；
2- [2- (4- chlorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone；
2- [2- (4- bromobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone；
2- [2- (4- trifluoromethyl benzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (4- trifluoro-methoxybenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (4- cyanobenzyls) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone；
2- [2- (4- nitrobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone；
2- [2- (3- luorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone；
2- [2- (3- chlorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone；
2- [2- (3- bromobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzo
[e] [1,3] thiazine -4- ketone；
2- [2- (3- trifluoromethyl benzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (3- trifluoro-methoxybenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (3- cyanobenzyls) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H- benzene
And [e] [1,3] thiazine -4- ketone；
2- [2- (2,4- difluorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone；
2- [2- (2,6- difluorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone；
2- [2- (3,4- difluorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone；
2- [2- (3,5- difluorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone；
2- [2- (2,4- dichloro benzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone；
2- [2- (3,4- dichloro benzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -4H-
Benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the fluoro- 3- chlorobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the fluoro- 4- chlorobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the fluoro- 4- bromobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the fluoro- 4- chlorobenzyl of 3-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the chloro- 4- luorobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the bromo- 4- luorobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the chloro- 4- luorobenzyl of 3-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the chloro- 3- trifluoromethyl benzyl of 4-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the fluoro- 4- trifluoromethyl benzyl of 3-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the bromo- 4- trifluoromethyl benzyl of 3-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the fluoro- 4- cyanobenzyls of 3-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the bromo- 4- nitrobenzyl of 3-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (the fluoro- 5- methylbenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (pyridine -2- ylmethyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (pyridin-3-yl methyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (pyridin-4-yl methyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone；
2- [2- (pyrimidine -2-base methyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitro -
4H- benzo [e] [1,3] thiazine -4- ketone.
The present invention further provides the preparation methods of we's formula (I) compound, include the following steps:
By formula (II) compound and formula (III) compound, in the presence of protonic solvent and be added acid binding agent, -5 DEG C~
It 60 DEG C, is stirred to react 0.5~10 hour, obtains formula (I) compound,
Wherein:
The definition of Z is the same as claim 1.The protonic solvent is selected from water, alcohol or alcohol-water mixed solvent；Described ties up
Sour agent is selected from triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Preferably, the preparation method of formula (I) compound of the present invention, comprising the following steps:
By formula (II) compound and formula (III) compound, in the presence of protonic solvent and acid binding agent is added, use is excessive
Formula (III) compound meets needs, at -5 DEG C~60 DEG C, with or without being stirred to react under pressure condition 0.5~10 hour, obtains formula
(I) compound.
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.
According to method shown in following reaction routes 2, formula (III) compound of another starting material of the invention can be prepared.
Reaction route 2:
In reaction route 2, Z is defined as the aforementioned.
Acid binding agent is added in non-protonic solvent, makes formula (IV) compound and formula (V) compound that condensation reaction, institute occur
The intermediate of generation sloughs protecting group with trifluoroacetic acid to get formula (III) compound is arrived without separation, directly.For this reaction
Non-protonic solvent be selected from acetonitrile, acetone, methylene chloride, chloroform, ether or hexamethylene；The acid binding agent is selected from carbonic acid
Sodium, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or triethylamine.
Formula (IV) compound and formula (V) compound as starting material are known compound, and there is supply of commodities in the country.
The present invention also provides contain treating tuberculosis composition of formula as defined above (I) compound as active constituent.Medicine
The weight ratio of the compounds of this invention that compositions contain in the composition is 0.1~99.9%, and pharmaceutically acceptable carrier exists
Weight ratio in composition is 0.1~99.9%.Pharmaceutical composition is to be suitble to medicinal dosage form to exist.Drug of the invention
Composition can be prepared into any pharmaceutical dosage form.Preferably, medicinal preparation be tablet, sugar coated tablet, film coated tablet,
Enteric coated tablet, sustained-release tablet, capsule, hard capsule, soft capsule, Duracaps, powder.
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.
When formula (I) reactive compound of the invention is used as the drug for the treatment of mycobacterium tuberculosis infection, preferably first
Stage gives the amount of 6~14mg/kg weight.But dosage can be with sick human needs, the seriousness of the infection to be treated, institute
It selects compound etc. and changes.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Generally, start treatment
Amount is 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 compounds shown in formula (I) or the pharmaceutical composition containing the compound to treat tuberculosis in preparation
Drug in application.
Tuberculosis of the present invention includes active tuberculosis, single resistant tuberculosis, more resistant tuberculosis and resistance to extensively
Multiple medicine tuberculosis.
Tuberculosis of the present invention includes pulmonary tuberculosis, the outer tuberculosis of lung.
As described above, the compounds of this invention 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.In particular, embodiment 1,4,7,9,20,28 and 32
Compound to the external activity of mycobacterium tuberculosis type strain H37Rv ATCC 27294 be 2-7 times of compound PBTZ169 with
On, the external activity to clinical separation strain MDR-MTB 20161 (to rifampin and Isoniazid-resistant) is compound PBTZ169
2-3 times or more.
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 (2- ethoxycarbonylmethyl group -2,8- diaza spiro [4.5] decane -8- base) -6- trifluoromethyl -8-
Nitro -4H- benzo [e] [1,3] thiazine -4- ketone
At room temperature, to the acetonitrile (15mL) of 2,8- azaspiro [4,5] decane -8- carboxylic acid tert-butyl ester (192mg, 0.88mmol)
Bromoacetate (181mg, 1mmol) and potassium carbonate (276mg, 2mmol) are added in solution, is stirred at room temperature 2 hours.To reaction solution
Middle addition distilled water (30mL), ethyl acetate extract (20mL × 3).It is associated with several layers of, anhydrous magnesium sulfate drying, concentration, through silicon
Plastic column chromatography (DCM:MeOH:NH3H2O=200:10:0.2) give light yellow oil (260mg).
At room temperature, the above grease (260mg) 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 (257mg, 0.8mmol), triethylamine (333 μ L, 2.4mmol), 40 DEG C are stirred 3 hours, concentration, silicagel column
It isolates and purifies, obtains light yellow solid, mp:116-118 DEG C.
1H NMR(400MHz,CDCl3) δ 9.14 (s, 1H), 9.78 (s, 1H), 4.24 (q, J=7.2Hz, 2H), 4.12
(brs,2H),3.88(brs,2H),3.39(s,2H),2.88(brs,2H),2.72(brs,2H),1.83-1.81(m,6H),
1.32 (t, J=7.2Hz, 3H).
13C NMR(400MHz,CDCl3) δ 170.48,166.57,161.73,143.95,134.26,133.39 (q, J=
3.5Hz), 129.60 (q, J=35.2Hz), 126.74,126.00 (q, J=3.5Hz), 122.50 (q, J=274.2Hz),
64.61,60.70,56.26,52.94,44.85,41.02,37.20,36.52,14.27。
HRMS-ESI(m/z):Calcd.for C21H24N4O5F3S(M+H)+:501.1414；Found:501.1417.
2. 2- of embodiment (2- tert-Butoxycarbonylmethyl -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, replaces the bromoacetate in embodiment 1 to get targeted with bromo-acetic acid tert-butyl
Close object.
1H NMR(400MHz,CDCl3)δ9.14(s,1H),9.78(s,1H),4.12(brs,2H),3.88(brs,2H),
3.39(s,2H),2.88(brs,2H),2.72(brs,2H),1.83-1.81(m,6H),1.42(s,9H)。
MS-ESI(m/z):529.1(M+H)+。
3. 2- of embodiment (2- carbobenzoxy methyl -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, replaces the bromoacetate in embodiment 1 to get target chemical combination with phenyl bromoacetate
Object.
1H NMR(400MHz,CDCl3)δ9.14(s,1H),9.78(s,1H),7.45-7.40(m,1H),7.37-7.30
(m,2H),7.08-7.00(m,2H),4.12(brs,2H),3.88(brs,2H),3.39(s,2H),2.88(brs,2H),2.72
(brs,2H),1.83-1.81(m,6H)。
MS-ESI(m/z):549.1(M+H)+.
4. 2- of embodiment (2- benzyloxycarbonyl-methyl -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, replaces the bromoacetate in embodiment 1 to get target chemical combination with benzyl acetate bromide
Object.
1H NMR(400MHz,CDCl3) δ 9.14 (s, 1H), 9.78 (s, 1H), 7.35-7.33 (m, 5H), 5.20 (s, 2H),
4.12(brs,2H),3.88(brs,2H),3.39(s,2H),2.88(brs,2H),2.72(brs,2H),1.83-1.81(m,
6H)。
MS-ESI(m/z):563.1(M+H)+.
5. 2- of embodiment (2- benzyl -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, replaces the bromoacetate in embodiment 1 to get light yellow solid with bromobenzyl, mp:
98-100℃。
1H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.79(s,1H),7.33(brs,5H),4.06(brs,
2H),3.80(brs,2H),3.58(brs,2H),2.54(brs,2H),2.48(brs,2H),1.68(brs,6H)。
13C NMR(400MHz,CD3OD) 167.46,162.81,144.49,134.59 (q, J=35.4Hz), 131.63,
129.48,129.39,128.31,65.44,59.41,52.92,40.53,28.87,26.64。
HRMS-ESI(m/z):Calcd.for C24H24N4O3F3S(M+H)+:505.1515；Found:505.1515.
6. 2- of embodiment [2- (4- luorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the bromoacetate in embodiment 1 to get light yellow solid with 4- fluorine bromobenzyl,
mp:154-156℃。
1H NMR(400MHz,CDCl3) δ 9.14 (d, J=2.2Hz, 1H), 8.79 (d, J=2.2Hz, 1H), 7.34 (brs,
2H), 7.05 (t, J=8.7Hz, 2H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H),
1.80(brs,6H)。
13C NMR(400MHz,CDCl3) δ 166.57,161.72,143.94,134.24,133.39,133.38 (q, J=
3.6Hz), 130.17,129.81,129.20 (q, J=35.4Hz), 126.74,126.00 (q, J=3.5Hz), 122.50 (q, J
=274.2Hz), 115.20 (d, J=21.2Hz), 59.35,53.15,44.79,40.72,37.28,37.28,
36.18.29.35。
HRMS-ESI(m/z):Calcd.for C24H23N4O4F4S(M+H)+:523.1421；Found:523.1411.
7. 2- of embodiment [2- (4- chlorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the bromoacetate in embodiment 1 to get target compound with 4- chlorine bromobenzyl.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.39 (d, J=8.4Hz, 2H), 7.22 (d,
J=8.4Hz, 2H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).
MS-ESI(m/z):539.1(M+H)+。
8. 2- of embodiment [2- (4- bromobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the bromoacetate in embodiment 1 to get target compound with 4- bromine bromobenzyl.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.85 (d, J=8.4Hz, 2H), 7.17 (d,
J=8.4Hz, 2H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).
MS-ESI(m/z):583.1,585.1(M+H)+.
9. 2- of embodiment [2- (4- trifluoromethyl benzyl) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get target with 4- trifluoromethyl bromobenzyl
Compound.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.54 (d, J=8.4Hz, 2H), 7.17 (d,
J=8.4Hz, 2H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).
MS-ESI(m/z):573.1(M+H)+.
10. 2- of embodiment [2- (4- trifluoro-methoxybenzyl) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get mesh with 4- trifluoromethoxy bromobenzyl
Mark compound.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.12 (d, J=8.4Hz, 2H), 6.89 (d,
J=8.4Hz, 2H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).
MS-ESI(m/z):589.1(M+H)+。
11. 2- of embodiment [2- (4- cyanobenzyls) -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, replaces the bromoacetate in embodiment 1 to get target chemical combination with 4- cyano-benzyl bromide
Object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.76 (d, J=8.4Hz, 2H), 7.46 (d,
J=8.4Hz, 2H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).
MS-ESI(m/z):530.1(M+H)+。
12. 2- of embodiment [2- (4- nitrobenzyl) -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, replaces the bromoacetate in embodiment 1 to get target chemical combination with 4- nitro bromobenzyl
Object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 8.32 (d, J=8.4Hz, 2H), 7.95 (d,
J=8.4Hz, 2H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).
MS-ESI(m/z):550.1(M+H)+。
13. 2- of embodiment [2- (3- luorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the bromoacetate in embodiment 1 to get target compound with 3- fluorine bromobenzyl.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.36-7.30(m,1H),7.08-6.90
(m,3H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):523.1(M+H)+。
14. 2- of embodiment [2- (3- chlorobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the bromoacetate in embodiment 1 to get target compound with 3- chlorine bromobenzyl.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.43-7.35(m,3H),7.18-7.10
(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):539.1(M+H)+。
15. 2- of embodiment [2- (3- bromobenzyl) -2,8- diaza spiro [4.5] decane -8- base] -6- trifluoromethyl -8- nitre
Base -4H- benzo [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the bromoacetate in embodiment 1 to get target compound with 3- bromine bromobenzyl.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.53-7.45(m,2H),7.28-7.15
(m,2H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):583.1,585.1(M+H)+。
16. 2- of embodiment [2- (3- trifluoromethyl benzyl) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get target with 3- trifluoromethyl bromobenzyl
Compound.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.50-7.40(m,3H),7.31-7.25
(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):573.1(M+H)+。
17. 2- of embodiment [2- (3- trifluoro-methoxybenzyl) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get mesh with 3- trifluoromethoxy bromobenzyl
Mark compound.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.25-7.18(m,1H),7.00-6.92
(m,3H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):589.1(M+H)+。
18. 2- of embodiment [2- (3- cyanobenzyls) -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, replaces the bromoacetate in embodiment 1 to get target chemical combination with 3- cyano-benzyl bromide
Object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.89-7.80(m,1H),7.79(s,1H),
7.59-7.45(m,1H),7.20-7.10(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49
(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):530.1(M+H)+。
19. 2- of embodiment [2- (2,4- difluorobenzyl) -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, replaces the bromoacetate in embodiment 1 to get targeted with 2,4- difluorobenzyl bromide
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.24-7.18(m,1H),7.24-7.15
(m,1H),6.96-6.88(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80
(brs,6H)。
MS-ESI(m/z):541.1(M+H)+。
20. 2- of embodiment [2- (2,6- difluorobenzyl) -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, replaces the bromoacetate in embodiment 1 to get targeted with 2,6- difluorobenzyl bromide
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.74-7.60(m,1H),7.40-7.30
(m,2H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):541.1(M+H)+。
21. 2- of embodiment [2- (3,4- difluorobenzyl) -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, replaces the bromoacetate in embodiment 1 to get targeted with 3,4- difluorobenzyl bromide
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.21-7.15(m,2H),6.95-6.88
(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):541.1(M+H)+。
22. 2- of embodiment [2- (3,5- difluorobenzyl) -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, replaces the bromoacetate in embodiment 1 to get targeted with 3,5- difluorobenzyl bromide
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),6.74-6.70(m,2H),6.65-6.60
(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):541.1(M+H)+。
23. 2- of embodiment [2- (2,4- dichloro benzyl) -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, replaces the bromoacetate in embodiment 1 to get targeted with 2,4- dichloro bromobenzyl
Close object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.70 (s, 1H), 7.26 (d, J=8Hz,
1H), 7.16 (d, J=8Hz, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80
(brs,6H)。
MS-ESI(m/z):573.1(M+H)+。
24. 2- of embodiment [2- (3,4- dichloro benzyl) -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, replaces the bromoacetate in embodiment 1 to get targeted with 3,4- dichloro bromobenzyl
Close object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.65 (d, J=8Hz, 1H), 7.40 (s,
1H), 7.20 (d, J=8Hz, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80
(brs,6H)。
MS-ESI(m/z):573.1(M+H)+。
25. 2- of embodiment [2- (the fluoro- 3- chlorobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with the fluoro- 3- chlorine bromobenzyl of 2-
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.37-7.30(m,1H),7.14-7.10
(m,2H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):557.1(M+H)+。
26. 2- of embodiment [2- (the fluoro- 4- chlorobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with the fluoro- 4- chlorine bromobenzyl of 2-
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.81-7.70(m,1H),7.20-7.10
(m,2H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):557.1(M+H)+。
27. 2- of embodiment [2- (the fluoro- 4- bromobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with the fluoro- 4- bromine bromobenzyl of 2-
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.62-7.50(m,1H),7.40-7.30
(m,1H),7.18-7.10(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80
(brs,6H)。
MS-ESI(m/z):601.1,603.1(M+H)+。
28. 2- of embodiment [2- (the fluoro- 4- chlorobenzyl of 3-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with the fluoro- 4- chlorine bromobenzyl of 3-
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.40-7.30(m,1H),7.18-7.10
(m,1H),7.00-6.91(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80
(brs,6H)。
MS-ESI(m/z):557.1(M+H)+。
29. 2- of embodiment [2- (the chloro- 4- luorobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with the chloro- 4- fluorine bromobenzyl of 2-
Close object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.81 (d, J=9.0Hz, 1H), 7.18-
7.10(m,1H),7.00-6.91(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),
1.80(brs,6H)。
MS-ESI(m/z):557.1(M+H)+。
30. 2- of embodiment [2- (the bromo- 4- luorobenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with the bromo- 4- fluorine bromobenzyl of 2-
Close object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.41 (d, J=9.0Hz, 1H), 7.18-
7.10(m,2H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):601.1,603.1(M+H)+。
31. 2- of embodiment [2- (the chloro- 4- luorobenzyl of 3-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with the chloro- 4- fluorine bromobenzyl of 3-
Close object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.81 (d, J=9.0Hz, 1H), 7.18-
7.10(m,1H),7.05-7.00(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),
1.80(brs,6H)。
MS-ESI(m/z):557.1(M+H)+。
32. 2- of embodiment [2- (the chloro- 3- trifluoromethyl benzyl of 4-) -2,8- diaza spiro [4.5] decane -8- 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, with the chloro- 3- trifluoromethyl bromobenzyl of 4- replace the bromoacetate in embodiment 1 to get
Target compound.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.44-7.30(m,3H),4.19(brs,
4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):607.1(M+H)+。
33. 2- of embodiment [2- (the fluoro- 4- trifluoromethyl benzyl of 3-) -2,8- diaza spiro [4.5] decane -8- 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, with the fluoro- 4- trifluoromethyl bromobenzyl of 3- replace the bromoacetate in embodiment 1 to get
Target compound.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.44-7.38(m,1H),6.94-6.85
(m,2H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):591.1(M+H)+。
34. 2- of embodiment [2- (the bromo- 4- trifluoromethyl benzyl of 3-) -2,8- diaza spiro [4.5] decane -8- 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, with the bromo- 4- trifluoromethyl bromobenzyl of 3- replace the bromoacetate in embodiment 1 to get
Target compound.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.44-7.38(m,2H),7.11-7.00
(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):651.1,653.1(M+H)+。
35. 2- of embodiment [2- (the fluoro- 4- cyanobenzyls of 3-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get target with the fluoro- 4- cyano-benzyl bromide of 3-
Compound.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.61-7.55(m,1H),7.23-7.15
(m,1H),7.20-7.15(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80
(brs,6H)。
MS-ESI(m/z):548.1(M+H)+。
36. 2- of embodiment [2- (the bromo- 4- nitrobenzyl of 3-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get target with the bromo- 4- nitro bromobenzyl of 3-
Compound.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 8.09 (d, J=8Hz, 1H), 7.89 (d, J
=8Hz, 1H), 7.70 (s, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80
(brs,6H)。
MS-ESI(m/z):628.1,630.1(M+H)+。
37. 2- of embodiment [2- (the fluoro- 5- methylbenzyl of 2-) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get target with the fluoro- 5- methyl bromobenzyl of 2-
Compound.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),7.17-7.05(m,3H),4.19(brs,
4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),2.31(s,3H),1.80(brs,6H)。
MS-ESI(m/z):537.1(M+H)+。
38. 2- of embodiment [2- (pyridine -2- ylmethyl) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with 2- bromo methyl cycloheptapyridine
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),8.50-7.45(m,1H),7.74-7.68
(m,1H),7.32-7.26(m,2H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49(brs,2H),1.80
(brs,6H)。
MS-ESI(m/z):506.1(M+H)+。
39. 2- of embodiment [2- (pyridin-3-yl methyl) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with 3- bromo methyl cycloheptapyridine
Close object.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.79(s,1H),8.59(s,1H),8.38-8.30(m,1H),
7.86-7.70(m,1H),7.37-7.30(m,1H),4.19(brs,4H),3.85(s,2H),2.70(brs,2H),2.49
(brs,2H),1.80(brs,6H)。
MS-ESI(m/z):506.1(M+H)+。
40. 2- of embodiment [2- (pyridin-4-yl methyl) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with 4- bromo methyl cycloheptapyridine
Close object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 8.55 (d, J=8.2Hz, 1H), 7.35 (d,
J=8.2Hz, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).
MS-ESI(m/z):506.1(M+H)+。
41. 2- of embodiment [2- (pyrimidine -2-base methyl) -2,8- diaza spiro [4.5] decane -8- 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, replaces the bromoacetate in embodiment 1 to get targeted with 2- bromomethyl pyrimidine
Close object.
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), 8.70 (d, J=8.2Hz, 2H), 7.39 (t,
J=8.2Hz, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).
MS-ESI(m/z):507.1(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, 1 compound of embodiment and 4 compound of embodiment are carried out
The solution of the two compounds containing various concentration is taken orally and awards male mice, dosage 0.1ml/10g by acute toxicity testing
Weight, count dead mouse amount respectively after 7 days, and the median lethal dose (LD of each compound is calculated with Bliss program50).As a result it is listed in table 2
In.
The Mouse oral acute toxicity of 2 compound of embodiment 1 and 4 of table
| Experimental compound | LD50(mg/kg) |
| Embodiment 1 | >2000 |
| Embodiment 4 | >2000 |
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 24, is added appropriate dextrin, Steviosin, dry granulation, whole grain, packing to get.
4 injection of embodiment
The compound 150g of Example 28 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 32 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 39 is spare as bulk pharmaceutical chemicals；Dripping pill matrix 200g is weighed, 80 DEG C of thawings are heated to,
It stirs evenly；It adds raw materials into excipient matrix while stirring, stirring 30min is allowed to uniformly, fluid temperature be kept to be not less than 60
℃；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 (4)
1. containing 2, the benzothiazine -4- ketone compounds of 8- diaza spiro [4.5] decane segment are 2- [2- (4- luorobenzyl) -
2,8- diaza spiro [4.5] decane -8- 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 according to claim 2, which is characterized in that the tuberculosis includes pulmonary tuberculosis, the outer tuberculosis of lung, active tuberculosis
Disease, single resistant tuberculosis, more resistant tuberculosis and extensive multi-drug resistance tuberculosis.
4. the pharmaceutical composition containing compound described in claim 1.
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| DE102014012546A1 (en) * | 2014-09-26 | 2016-03-31 | Martin-Luther-Universität Halle-Wittenberg | Antimycobacterially active substances, process for their preparation and their use |
| CN105622596A (en) * | 2016-02-19 | 2016-06-01 | 浙江司太立制药股份有限公司 | Benzothiazine-4-ketone compound containing alkoxyimino azacyclo-fragments and preparation method of benzothiazine-4-ketone compound |
| CN103508980B (en) * | 2012-06-14 | 2016-07-06 | 四川大学 | Benzothiazine-4-ketone derivatives and its production and use |
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| CN103508980B (en) * | 2012-06-14 | 2016-07-06 | 四川大学 | Benzothiazine-4-ketone derivatives and its production and use |
| DE102014012546A1 (en) * | 2014-09-26 | 2016-03-31 | Martin-Luther-Universität Halle-Wittenberg | Antimycobacterially active substances, process for their preparation and their use |
| CN105622596A (en) * | 2016-02-19 | 2016-06-01 | 浙江司太立制药股份有限公司 | Benzothiazine-4-ketone compound containing alkoxyimino azacyclo-fragments and preparation method of benzothiazine-4-ketone compound |
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