CN107880023A - Fluoroquinolones amido derivative and application thereof - Google Patents
Fluoroquinolones amido derivative and application thereof Download PDFInfo
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- CN107880023A CN107880023A CN201711102862.5A CN201711102862A CN107880023A CN 107880023 A CN107880023 A CN 107880023A CN 201711102862 A CN201711102862 A CN 201711102862A CN 107880023 A CN107880023 A CN 107880023A
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- 0 **C1=C*(*)c(nc(*(C*C2)CC2*(C(*C*N)O)C2CC2)c(N)c2)c2C1=O Chemical compound **C1=C*(*)c(nc(*(C*C2)CC2*(C(*C*N)O)C2CC2)c(N)c2)c2C1=O 0.000 description 2
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Abstract
The invention belongs to medicinal chemistry art, and in particular to a kind of fluoquinolone analog derivative and application thereof.The present invention obtains compound shown in Formulas I by carrying out structural modification to FQNS, the compound of the present invention is not only able to treat infection caused by mycobacterium tuberculosis and common bacteria, and also withholding bacterium, citrus pathogenic bacteria, niacinamide N transmethylases (NNMT) and the PPI of interleukins IL 17 to bacterium has inhibitory activity.Preparation of compounds of the invention is easy to operate, mild condition, obtain antibacterial activity enhancing, water-soluble raising, numerous compounds of toxic side effect reduction, it is expected to reduce dosage, shortens treatment cycle, improve patient compliance, new molecule type and Research Thinking is provided for tubercular drugs and other diseases research.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of fluoroquinolones amido derivative and application thereof.
Background technology
Tuberculosis (Tuberculosis, TB) is one kind by mycobacterium tuberculosis (Mycoabcterium
Tuberculosis, MTB) the caused chronic infectious disease based on respiratory infectious.MTB is mainly caused outside pulmonary tuberculosis,
Human body other whole organs can also be involved, be one of major disease for seriously endangering human health, and the whole world is permanent common closes
The public health problem and social concern of note.During the medication of antituberculotic, resistant tuberculosis (drug-resistant
Tuberculosis, DR-TB) especially multi-drug resistance tuberculosis produce and gradually increasing, containment resistant tuberculosis have become
Very urgent research topic.
Global tuberculotherapy result with experience have shown that, no matter how powerful single antituberculotic bactericidal activity is, no
Pipe is old medicine (such as streptomysin or isoniazid) or the new drug (such as shellfish reaches quinoline and De Lamani) of exploitation in nearly 2 years, as long as single
Use, corresponding antibody-resistant bacterium always occurs.Therefore, the tuberculosis therapy scheme that WHO recommends all is different type clinic tuberculosis medicine
The combination of thing.《WHO resistant tuberculosis treatment guidelines (2016 more new edition)》The therapeutic scheme of the resistant tuberculosis of recommendation has containing 5 kinds
Imitate antituberculotic.Although current cure rate lungy can reach more than 90%, because treatment course is long, adverse drug
The drawback such as big is reacted, is voluntarily discontinued plus patient, drug compliance is poor, lacks the reasons such as necessary supporting step, this standard
The use of scheme is faced with lot of challenges.In addition, resistant tuberculosis continuously emerges, make treatment difficulty lungy bigger.Therefore,
New antibacterials are researched and developed, optimizing therapeutic regimen, curative effect is improved and shortens treatment cycle, curative compliance is improved, to tuberculosis
The defence and treatment of disease and other diseases are significant.
Human body is a complicated organism in itself, single to act on a certain target spot and treated in more mechanism diseases,
Its action effect is not highly satisfactory, thereby increases and it is possible to causes target is mutated or bypass is raised etc., and then produces serious pair
Effect, body is finally set to strengthen the tolerance of medicine, therapeutic effect is difficult to be ensured for a long time.To solve this problem, base
The note of people is caused in the Mutiple Targets medicine theory for improving curative effect and (or) improving the overall goal of security and rationally designing
Meaning.Mutiple Targets medicine can act on the related multiple target spots of disease, produces a variety of pharmacological activity, effectively adjusts whole cell
Complicated system, the relation in signal transducting system between each member is not exclusively eliminated, reduces side effect.According to composition and effect
The difference of target spot, Mutiple Targets can be divided into " multiple medicine Mutiple Targets " medicine (drug combination), " more prescription target spots " medicine (multicomponent medicine
Thing), the class of " single medicine Mutiple Targets " medicine three, wherein all refer to two or more medicines during preceding two classes drug administration, due to medicine it
The complexity of interphase interaction, both administering modes may have the difficulty of dosage control to increase, compatibility of drugs risk increases,
The shortcomings of compliance of patient is deteriorated, therefore, single medicine Mutiple Targets compound design is increasingly becoming the focus direction of new drug design.Closely
Nian Lai, there is the heterozygosis of bioactive molecule (i.e.：By two or more different pharmacophore combination shapes of different bioactive molecules
Into recruit) as one of study hotspot of medicinal chemistry art.To original medicine or with preferably active candidate's medicine
Thing and its active fragment carry out structural modification, are one kind strategies for developing Antitubercular medicine.
A kind of synthetic antibacterial drug that QNS is made up of aromatic rings such as pyridine ketone acid parallel connection benzene or pyridines, has
Unique mechanism of action, can quickly kill bacterium, plus its outstanding pharmacokinetic property, already as very popular
Clinical treatment medication.Fluoquinolone (FQs) class medicine is third and fourth generation QNS developed in recent years, is had fine
Early stage bactericidal activity, it is one of key agents of current treatment resistant tuberculosis, is used for more as two wires anti-tuberculosis drugs resistance to
Medicine tuberculosis or the auxiliary treatment to an intolerable tuberculosis patient of line anti-tuberculosis drugs.FQs class medicines not only have
Have preferable anti-tubercular, and also good pharmacokinetic property, as oral administration biaavailability is good, blood concentration compared with
Height, Tissue distribution are wide, drug half-life length, while adverse reaction is less, is not handed over other types of anti-mycobacteria medicine
Pitch drug resistance.
Isoniazid (INH) is a classical anti-tuberculosis drugs, and its action target spot is InhA.It is used for tuberculosis from nineteen fifty-two
Since disease treatment, INH is still one for the treatment of maximally effective first-line drug of tuberculosis.It has recently been demonstrated that to INH hydrazides end
Bit amino is modified, and either forms hydrazone class or heterocycle compound, or using heterocycle is Linker by hydrazides end position ammonia
Base is coupled with other pharmacophoric groups forms new molecule, there is preferable Killing Mycobacterium Tuberculosis activity.It can be seen that isoniazid is entered
Row structural modification has preferable Prospect of R ＆ D.It is small, inexpensive, active high, special containing heterocycle, mechanism of action in view of INH molecular weight
Very, and various ways and other molecular conjugates can be used, therefore by INH and its variant isonicotinic acid preferably as active fragment and fluorine
Quinolone active fragment connects, and is expected to obtain single medicine Mutiple Targets medicine with treatment resistant tuberculosis activity.
Pyrazinamide (PZA) is a kind of unique line anti-tuberculosis drugs：Itself activity is unsatisfactory, but and its
When its anti-tuberculosis drugs is applied in combination, very strong bactericidal activity and synergy are presented；Most researchers think, PZA
Be also prodrug as INH, through mycobacterium tuberculosis specificity PZA activate enzyme activition, produce pyrazine acid (POA).Therefore, PZA
With POA active fragment is can also serve as to be connected with fluoquinolone active fragment, be expected to obtain another kind of new having treat it is resistance to
Single medicine Mutiple Targets medicine of medicine tuberculosis activity.
The content of the invention
The present invention chooses representative FQNS and passes through attachment structure and isoniazid/isonicotinic acid or pyrazine
Acid amides/pyrazine acid is connected with chemical bond, can be with the bioactive molecule for obtaining antibacterial activity enhancing, toxic side effect reduces simultaneously
Pulmonary tuberculosis and the infection of secondary common bacteria are treated, so as to reduce dosage and medicament categories, shorten treatment cycle,
Improve patient compliance.Make people pleasantly surprised, the Mutiple Targets screening of medicine is carried out in the compound for designing the application and preparing
During, have been surprisingly found that these compounds withhold bacterium, citrus pathogenic bacteria, NNMT (NNMT) and white to bacterium
Cytokine IL-17PPI is inhibited, has further researching value.
The present invention provides a kind of compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxides shown in formula I
Or their pharmaceutically acceptable salt：
Wherein X is selected from：C1-C6 alkyl；C3-C6 cycloalkyl；Substituted or unsubstituted C6-C10 aryl, on the aryl
Substituent for one or more, be independently selected from：Halogen；Amino；Hydroxyl；C1-C6 alkyl；C3-C6 cycloalkyl；
Z is selected from：N or C-R7；R7It is selected from：H；C1-C6 alkoxy or halogens；
R1And R2It is each independently selected from：H；C1-C6 alkyl；C1-C6 haloalkyls；C1-C6 alkoxies；Halogen；Hydroxyl；C1-
C6 alkyl amino；Amino or cyano group；
R3、R4The substituted or unsubstituted 5-7 members saturation being collectively forming with the group being connected at least containing 1 N atom is miscellaneous
Ring, the substituent on the saturated heterocyclic is one or more, is independently selected from：Halogen；Amino；Hydroxyl；C1-C6 alkyl；C3-C6
Cycloalkyl；R5Selected from H, C1-C6 alkyl；
Or R3、R5The 5-7 member saturated heterocyclics containing 2 N atoms are collectively forming with the group being connected；R4It is selected from：H；Halogen
Element；Amino；Hydroxyl；C1-C6 alkyl；
A is selected fromCarboxyl or halogen
Element；Het is the 5-7 member hetero-aromatic rings containing at least one nitrogen-atoms；R6 is selected from H, C1-C6 alkyl；
N, k are independently selected from the integer for 0 to 3.
Preferably, the present invention also provides compound, its raceme, stereoisomer, change as shown in Formula II, formula III
Isomers, nitrogen oxides or their pharmaceutically acceptable salt：
Wherein X is selected from：C1-C6 alkyl；C3-C6 cycloalkyl；Substituted or unsubstituted C6-C10 aryl, on the aryl
Substituent for one or more, be independently selected from：Halogen；Amino；Hydroxyl；C1-C6 alkyl；C3-C6 cycloalkyl；
Z is selected from：N or C-R7；R7It is selected from：H；C1-C6 alkoxy or halogens；
R1And R2It is each independently selected from：H；C1-C6 alkyl；C1-C6 haloalkyls；C1-C6 alkoxies；Halogen；Hydroxyl；C1-
C6 alkyl amino；Amino or cyano group；
R4It is selected from：H；Halogen；Amino；Hydroxyl；C1-C6 alkyl；
R5Selected from H, C1-C6 alkyl；
A is selected fromOr halogen；
Het is the 5-7 member hetero-aromatic rings containing at least one nitrogen-atoms；R6 is selected from H, C1-C6 alkyl；
N, k are independently selected from the integer for 0 to 3；
M is 1 or 2.
As further preferred, A is selected from following structure：
In preparation example/embodiment of some classifications, present invention also offers change shown in formula IV, Formula V, Formula IV or Formula VII
Compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt：
X is selected from：Methyl；Ethyl；Propyl group；Butyl；Cyclopropyl；The substituted or unsubstituted phenyl of halogen；
Z is selected from：N or C-R7；R7It is selected from：H；Methoxyl group；Ethyoxyl；Fluorine or chlorine；
Wherein R1And R2It is each independently selected from：H；Methyl；Ethyl；Trifluoromethyl；Methoxyl group；Ethyoxyl；Halogen；Hydroxyl or
Amino；
R4 is selected from：H；Halogen；Amino；Hydroxyl；Methyl or ethyl；
R5 is selected from H；Methyl or ethyl；
A is selected from
N is 1 or 2 or 3；
M is 1 or 2.
In some preparation example/embodiments, the present invention is also provided such as Formula VIII, the compound shown in Formula IX, its raceme,
Stereoisomer, dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt；
X is selected from：Methyl；Ethyl；Propyl group；Butyl；Cyclopropyl；The substituted or unsubstituted phenyl of halogen；
Z is selected from：N or C-R7；R7Selected from H；Methoxyl group；Ethyoxyl；Fluorine or chlorine；
R4It is selected from：Halogen；Amino；Hydroxyl；Methyl or ethyl；
R5Selected from H；Methyl or ethyl；
N is 1 or 2 or 3；
M is 1 or 2.
The present invention also provides the compound as described in preparation example/embodiment, its raceme, stereoisomer, tautomerism
Body, nitrogen oxides or their pharmaceutically acceptable salt.
A kind of pharmaceutical composition, including above-mentioned any compound, its raceme, alloisomerism is also claimed in the present invention
Body, dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt.
Preferably, the present invention any compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or
Their pharmaceutically acceptable salt, pharmaceutically acceptable any formulation can be made, i.e. pharmaceutical composition of the invention can also wrap
Include pharmaceutically acceptable carrier and/or auxiliary agent.
Preferably, the present invention any compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or
Reagent for clinical diagnosis (box) can be made in their pharmaceutically acceptable salt.
Preferably, can as needed by one or more other active components with the present invention any compound, its
Compound medicine is made in raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt.
Above-mentioned any compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxidation is also claimed in the present invention
The purposes of thing or their pharmaceutically acceptable salt in the medicine for preparing treatment disease, the disease is selected from bacterium and bacterium withholds
Bacterium infection associated diseases, citrus pathogenic infection associated diseases, inflammatory disease or tumour.The bacterium includes but is not limited to：Knot
Core mycobacteria, staphylococcus aureus, Escherichia coli, pseudomonas aeruginosa or detection of Salmonella.The citrus pathogenic bacteria are selected from：Mandarin orange
Tangerine ulcer bacteria；Citrus brown patch germ or citrus green mold bacterium；The inflammatory disease is the related inflammatory diseases of IL-17, preferably class
Rheumatic arthritis (RA), asthma, multiple sclerosis (MS), chronic obstructive pulmonary disease (COPD), acute respiratory distress synthesis
Levy (ARDS), idiopathic pulmonary fibrosis (IPF), inflammatory bowel disease (IBD), Crohn's disease, uveitis, macular degeneration,
Colitis, psoriasis, Wallerian degeneration, antiphospholipid antibody syndrome (APS), acute coronary syndrome, ISR, Atherosclerosis
Change, relapsing polychondritis (RP), acute or chronic hepatitis, failure plastic surgery implantation, glomerulonephritis, lupus and
Autoimmune disease.The tumour is selected from：Lung cancer, kidney, carcinoma of the colon and rectum, nasopharyngeal carcinoma, breast cancer, cancer of pancreas, liver cancer, stomach
Cancer, glioma, carcinoma of urinary bladder and OSCC or medulloblastoma.
The present invention is also claimed above-claimed cpd, stereoisomer or its pharmaceutically acceptable salt and is preparing diagnosing tumor examination
Application in agent.
Term is defined and explained：
Unless otherwise indicated, the group described in present specification and claims and term definition, including its work
For the defining of example, it is exemplary define, preferably particular compound is determined in definition, the definition described in form, embodiment
Justice etc., it can be combined and combine each other.Group definition and compound structure after such combination and combination, should
Belong in the range of present specification record.
Unless otherwise indicated, when " the compounds of this invention " used herein or " compound of the invention ", at least it is intended to
Covering the compound shown in formula (I), its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmacy can connect
By salt.
Term " dynamic isomer " refer to because in molecule a certain atom in two rapid movements in position and caused by functional group
Isomers.The compounds of this invention can show tautomerism.Tautomeric compound may have two or more can
The species mutually converted.The migration of prototropic tautomeric body hydrogen atom of covalent bonding between two atoms.Change
Isomers typically exists with equilibrium form, attempts to generally produce a kind of mixture when separating single dynamic isomer, its physics and chemistry
The mixture of matter and compound is consistent.The position of balance depends on the chemical characteristic of intramolecular.For example, in many aliphatic aldehydes
In ketone such as acetaldehyde, ketone type is dominant；And in phenol, enol form is dominant.All tautomerisms of inclusion compound of the present invention
Form.
Term " halogen " refers to F, Cl, Br and I.In other words, F, Cl, Br and I can be described as " halogen " in this manual.
Term " C1-C6 " is interpreted as the preferred straight or branched saturation monovalent hydrocarbon for representing to have 1-6 carbon atom, example
Such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, isopentyl, 2- methyl fourths
Base, 1- methyl butyls, 1- ethyl propyls, 1,2- dimethyl propyls, neopentyl, 1,1- dimethyl propyls, 4- methyl amyls, 3- first
Base amyl group, 2- methyl amyls, 1- methyl amyls, 2- ethyl-butyls, 1- ethyl-butyls, 3,3- dimethylbutyls, 2,2- dimethyl
Butyl, 1,1- dimethylbutyls, 2,3- dimethylbutyls, 1,3- dimethylbutyls or 1,2- dimethylbutyls etc. or theirs is different
Structure body.
Term " the 5-7 members saturated heterocyclyl containing 1 or 2 N atom " can include but is not limited to：5 yuan of rings, such as pyrroles
Alkyl, imidazolidinyl, pyrazolidinyl；Or 6 yuan of rings, such as piperidyl, morpholinyl, thio-morpholinyl or piperazinyl；Or 7 yuan of rings, such as
Nitrogen heterocyclic heptyl.
Term " C6-C10 aryl " is interpreted as the preferred armaticity or partial aromatic for representing to have 6-10 carbon atom
Monocyclic, bicyclic or tricyclic hydrocarbon ring, particularly the ring (" C with 6 carbon atoms6Aryl "), such as phenyl；Or xenyl, or
Person is the ring (" C with 9 carbon atoms9Aryl "), such as indanyl or indenyl, or the ring (" C with 10 carbon atoms10
Aryl "), such as tetrahydro naphthyl, ihydro naphthyl or naphthyl.
Term " the 5-7 members hetero-aromatic ring containing at least one nitrogen-atoms " is interpreted as with 5-7 annular atom and comprising at least
1N atoms, especially, heteroaryl are selected from pyrrole radicals, imidazole radicals, pyrazolyl, isoxazolyls, isothiazolyl, triazol radical, pyridine
Base, pyridazinyl, pyrimidine radicals, pyrazinyl or triazine radical etc..
The number range that present specification and claims are recorded, when the number range is defined as " integer ",
Each integer in the range of should be understood to describe two end points of the scope and being somebody's turn to do.It is for example, " any whole in 0-4
Number " should be understood to describe 0,1,2,3,4 each integer.
Compound pharmaceutically acceptable salt mentioned by the present invention can be ackd salt or basic salt.Pharmacy
Upper acceptable salt can be the acid with compound of the invention alkaline enough with nitrogen-atoms for example in chain or ring
Addition salts, such as the acid-addition salts formed with following inorganic acid：Such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, burnt sulphur
Acid, phosphoric acid or nitric acid, or disulfate, or the acid-addition salts formed with following organic acid：Such as formic acid, acetic acid, acetyl second
Acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, laurate, benzoic acid, salicylic acid, 2- (4- hydroxyls
Base benzoyl) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, 3- hydroxy-2-naphthoic acids, nicotinic acid, flutter acid, pectin ester
Acid, persulfuric acid, 3- phenylpropionic acids, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acids, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, ten
Dialkyl group sulfuric acid, ethyl sulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid,
Tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, butanedioic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D- glucose
Acid, mandelic acid, ascorbic acid, glucoheptose, phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or thiocyanic acid.In addition, tool
The pharmaceutically acceptable salt for having the another kind of compound of the invention acid enough suitable be alkali metal salt (such as sodium salt or
Sylvite), alkali salt (such as calcium salt or magnesium salts), ammonium salt, or with provide the acceptable cation of physiology organic base shape
Into salt, such as with following material formed salt：Sodium ion, potassium ion, N-METHYL-ALPHA-L-GLUCOSAMINE, dimethyl aminoglucose, ethyl Portugal
Osamine, lysine, dicyclohexylamine, 1,6- hexamethylene diamines, monoethanolamine, aminoglucose, meglumine, methyl amimoacetic acid, serinol, trihydroxy first
Base aminomethane, amino-propanediol, 1- amino -2,3,4- butantriols.
The compounds of this invention preferably in unmodified form or preferably with conventional use of adjuvant one in the preparation of this area
Inside and outside application is played, therefore can be processed in a known way, obtains such as liquid preparation (propellant, emulsion, suspension
Agent, solution, emulsifiable concentrate, Solution Concentrate), semisolid preparation (such as creme, ointment, patch, gel,
Liposomal formulation) and solid pharmaceutical preparation (such as powder, granule, tablet etc.).
The example of term pharmaceutically acceptable carrier and/or auxiliary agent is：Carbohydrate, such as lactose, sucrose, mannitol and mountain
Pears alcohol；Starch, such as cornstarch, tapioca and potato starch；Cellulose and its derivates, such as carboxymethyl cellulose
Sodium, ethyl cellulose and methylcellulose；Calcium phosphate, such as Dicalcium Phosphate and tricalcium phosphate；Sodium sulphate；Calcium sulfate；Poly- second
Alkene pyrrolidone；Polyvinyl alcohol；Stearic acid；Alkali earth metal stearate, such as magnesium stearate and calcium stearate；Plant oil,
Such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil；Nonionic, cation and anionic surfactant；Poly- second
Glycol；Aliphatic alcohols；With hydrolyzed cereal solids and other nontoxic compatible fillers, adhesive, disintegrant, buffering
The commonly used auxiliary material in pharmaceutical preparation such as agent, preservative, antioxidant, lubricant, colouring agent.
The beneficial effects of the present invention are：
1) present invention has carried out structural modification and improvement to FQNS, obtains antibacterial activity enhancing, the secondary work of poison
With the new bioactive molecule of reduction.The compound of the present invention shows good In Vitro Bacteriostatic, to mycobacterium tuberculosis, greatly
Enterobacteria, the bacteriostatic activity of staphylococcus aureus are suitable with FQNS.The compound of the present invention is used in medicine
It is expected to reduce dosage and combination variety, shortens treatment cycle, improve patient compliance, is the medicine of tuberculosis and other diseases
Thing research provides new molecule type and Research Thinking.
2) compound of the invention also bacterium is withheld bacterium, citrus pathogenic bacteria, NNMT (NNMT) and
Interleukins IL-17PPI is inhibited, has further researching value.
Embodiment
It detailed description of a preferred embodiment of the present invention will be given below.The reality of unreceipted actual conditions in preferred embodiment
Proved recipe method, generally according to normal condition, illustrated embodiment is to preferably be illustrated to present disclosure, but is not
Present disclosure is only limitted to illustrated embodiment.So those skilled in the art according to foregoing invention content to embodiment party
Case carries out nonessential modifications and adaptations, still falls within protection scope of the present invention.
Target compound prepares embodiment
The synthesis of Formula X I series compounds：
Preparation example 1-24
1mmol sand star and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol
NaHCO3, after 20min, 2.5mmol chloros acyl chlorides (Cl- (CH are added dropwise with constant pressure funnel2)nCOCl, n=1,2,3) DCM
(2mL) solution (rate of addition is about 1d/2s), drip and finish sustained response under ice bath (during 2-CC, moving to -5 DEG C), TLC tracking and monitorings
Terminate to reaction.Stop stirring, add H2O 15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, if having
Solid is then stood, filtered, and filter cake is washed 3 times with DCM, and filter cake remains to be further purified；Filtrate moves to separatory funnel, liquid separation, aqueous phase
Extracted (15mL × 1) with DCM, merge organic phase, saturation NaCl solution washing (15mL × 1), collect organic phase, anhydrous Na2SO4
Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains sterling, vacuum drying, obtain intermediate Formula X.
The intermediate Formula X composite result of table 1
Embodiment 1-35
Intermediate 1mmol, 5mL toluene, the 2mmol Et of Formula X are added in 100mL round-bottomed flasks3N, 20-30min is stirred,
2mmol isonicotinic acid (INA) or pyrazine carboxylic acid (POA) are added, moves in 110 DEG C~120 DEG C oil bath pans and is flowed back instead after 10min
Should, TLC monitors complete to reaction.Reaction solution is spin-dried for Rotary Evaporators Rotary Evaporators, adds 30mL DCM stirring and dissolvings,
Filter, filter cake is washed 3 times with DCM, and filtrate is washed (15mL × 1) with 10% citric acid solution, collects organic phase, anhydrous Na2SO4Dry.
Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains sterling, and vacuum drying obtains target product.
The target compounds of formula XI composite results of table 2
The target compounds of formula XI composite results of table 3
The synthesis of Formula X II series compounds：
Embodiment 36-41
2mmol isoniazid, 4mmol NaHCO are sequentially added in 100mL round-bottomed flasks3With 5mL DCM, stir under the conditions of -5 DEG C
After mixing 20min, 3mmol chloracetyl chlorides solution (rate of addition is about 1d/2s) is added dropwise with constant pressure funnel, is held under the conditions of -5 DEG C
Continuous reaction, TLC tracking and monitorings to reaction terminate.Under stirring state, DCM-CH is added3OH solution (VDCM:VCH3OH=2：1) to anti-
Answer solid in bottle no longer to reduce, stand, filter, filter cake DCM-CH3OH solution washs 3 times, filtrate anhydrous Na2SO4Dry,
Rotary Evaporators are spin-dried for obtaining crude product, then add 5mL DCM stirring 20min, filter, filter cake washes 3 times, and vacuum with DCM
Dry, it is standby to obtain intermediate.
1mmol sand star, 4mmol Et are sequentially added in 100mL round-bottomed flasks3N and 2mL DMF, added after stirring 20min
Above-mentioned intermediate, stirring reaction under the conditions of moving to 60 DEG C after 10min, TLC, which is monitored to reaction, to be terminated.10mL is added under stirring state
The ice-cold saturated common salt aqueous solution, and pH=8 or so is adjusted with 1N HCl solutions, filtering, filtrate extracts (10mL × 2) with DCM,
Merge organic phase, use anhydrous Na2SO4Dry, Rotary Evaporators are spin-dried for, and column chromatography purifies together with filter cake, obtains target compound
Formula X II.
The target compounds of formula XII composite results of table 4
The synthesis of Formula X V series compounds：
Preparation example 25-40
Amino acid (50mmol), methanol 100mL are added in reaction bulb, SOCl is slowly added dropwise under ice bath2(125mmol),
Drop finishes, and is transferred to 60 DEG C of stirred in water bath back flow reactions, TLC monitorings are until reaction terminates.Vacuum rotary steam removes methanol and major part
SOCl2, methanol 20mL is added, is rotated again to eliminate SOCl as far as possible2, vacuum drying, obtain corresponding amino acid methyl ester salt
Hydrochlorate.
INA/POA (20mmol), HOBt (24mmol), DCC (24mmol), DCM (20mL) are sequentially added in reaction bulb,
Et is added after stirring 10min3N (60mmol, DIPEA is added when amino acid is alanine) under ice bath, and sweet ammonia is added after 0.5~1h
Acid/alanine methyl ester hydrochloride (22mmol), TLC, which is monitored to reaction, to be terminated.Refrigerator freezing 2h is put into, is filtered, filter cake is washed with DCM
Wash, filtrate is with saturation Na2CO3The aqueous solution is washed (20mL × 2), and aqueous phase is extracted (30mL × 3) with DCM, merges organic phase, anhydrous
Na2SO41h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains Formula X III compounds.
Preparation example 25-32 intermediates (15mmol), CH are sequentially added in reaction bulb3OH-H2O(V CH3OH:V H2O=3:
1) solution (15mL), LiOHH is added under ice bath2O (45mmol), stirring, TLC, which is monitored to reaction, to be terminated.Rotary Evaporators will
CH3OH is removed, and with 4N HCl solutions regulation pH=3 or so under ice bath, is had a large amount of white solids to separate out, is filtered, filter cake uses filtrate
Wash 2 times, acetone is washed 2 times, 50 DEG C of drying, obtains Formula X IV compounds.
The intermediate Formula X formula III XIV composite results of table 5
Embodiment 42-105
HBTU/TBTU methods：Sequentially added in reaction bulb Formula X IV compounds (1mmol), HBTU/TBTU (1.2mmol),
DCM(3mL)、Et3N (adding DIPEA under ice bath when 3mmol, Ala are Linker), Sha Xing (1mmol), temperature control stirring, TLC prisons
Survey to reaction and terminate.DCM 20mL are added, move to separatory funnel, saturation Na2CO3The aqueous solution is washed (20mL × 1), and 0.5N HCl are molten
Liquid is washed (20mL × 1), saturated common salt washing (20mL × 1), anhydrous Na2SO41h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains
Formula X V series compounds.
EDCI-HOBt methods：Formula X IV compounds (1mmol), HOBt (1.2mmol), EDCI are sequentially added in reaction bulb
(1.2mmol), DCM (3mL), Et3N (is fed) when 3mmol, Ala are Linker under ice bath, and husky star is added after stirring 0.5~1h
(1mmol), TLC, which is monitored to reaction, to be terminated.DCM 20mL are added, separatory funnel are moved to, with saturation Na2CO3The aqueous solution washes (20mL
× 1), 0.5N HCl solutions are washed (20mL × 1), saturated common salt washing (20mL × 1), anhydrous Na2SO4Dry 1h, Rotary Evaporators
It is spin-dried for, column chromatography obtains Formula X V series compounds.
The Formula X V series compound composite results of table 6
The Formula X V series compound composite results of table 7
External activity effect example
1st, the inhibitory activity test of mycobacterium tuberculosis
Mycobacterium tuberculosis (M.tuberculosis) is to cause pathogen lungy.Each organ of whole body can be invaded, but
Using pulmonary tuberculosis as most common (because happiness oxygen).Tuberculosis is still important infectious disease so far.Estimate 1/3 infection in world population
Mycobacterium tuberculosis.According to WHO, 8,000,000 new cases generation is there are about every year, at least 3,000,000 people die from the disease.
The inhibitory activity test of mycobacterium tuberculosis (H37Rv reference cultures) has been carried out to target compound：From tuberculosis
Reference culture H37Rv, has carried out the full cytoactive test (Primary SP) of single concentration, and the series compound for determining the present invention exists
Inhibiting rate under 20 μM of sample concentration, the test sample dilution (more concentration, CRC) higher to activity carry out secondary screening afterwards
(Secondary assays), measure suppress the lowest concentration of drug (MIC) of H37Rv growths and the cell toxicant to HELA cells
Property, with half-inhibition concentration (IC50) represent.
Pass through(the chemiluminescent homogeneous immunological detection reagent box based on microballon, PerkinElmer) is surveyed
The mycobacterium tuberculosis inhibitory activity for the compound that sets the goal.And useLuminescent Cell
Viability Assay(Luminescence method cell viability detection kit) test sample is tested to HELA cells
Cytotoxicity (half-inhibition concentration IC50)。
Anti-tubercular the selection result shows that the inhibiting rate of series compound of the invention under 20 μM of sample concentration exists
More than 80%.More concentration inhibitory activity detections have been carried out to compound of the part inhibitory activity more than 90%, have as a result been shown, except reality
Outside the compound for applying example 90, the MIC value of remaining high-activity compound is below 10 μM, especially embodiment 33,34,17,4
MIC value as little as 0.16,0.23,0.24,0.35 μM.Cytotoxicity test (HELA Cytotox activity) shows, these high activities
Relative inhibition Rel IC of the compound to HELA cells50>20.0 μM, there is relatively low cytotoxicity.Specifically it is shown in Table 8.
The compound of table 8 is to mycobacterium tuberculosis bacteriostatic activity
2nd, Conventional bacteria and the bacteriostatic activity of fungi are tested
Bacterium infection is growth and breeding in pathogenic bacteria or conditioned pathogen intrusion blood circulation, produces toxin and other metabolism productions
Acute systemic infection caused by thing, clinically characterized by shiver with cold, high fever, fash, arthralgia and hepatosplenomegaly, partly may be used
Infectious is suffered a shock and migrates venereal disease stove.The most of malnutritions of lunger, influenceed for a long time by immune suppression agent treatment, patient
Constitution dies down, and body immunity declines, easily concurrent a variety of Conventional bacteria infectious diseases.In order to verify the compound of the present invention
Whether there is Mutiple Targets activity, the present invention has carried out bacteriostatic activity test.
Minimal inhibitory concentration (MIC) determines
Test strain：Staphylococcus aureus (S.aureus) ATCC29213；Escherichia coli (E.coli) are clinically separated
Strain.
Open 96 orifice plates of bacterium of having gone out under aseptic condition, the 1st hole adds the M-H meat soups of 200 μ L drug containing, and final concentration of 32
μg/mL.Remaining 11 holes add 100 μ L blank cultures.100 μ L are accurately drawn from the 1st hole with liquid-transfering gun and add the second hole, blow
Beat and mix, then draw 100 μ L to the 3rd hole from the 2nd hole again, the rest may be inferred, until the 10th hole, 100 μ L is inhaled after mixing and are discarded.This
When per the drug concentration in hole be 64,32,16,8,4,2,1,0.5 μ g/mL.Last 2 hole not drug containing, one is used as bacterial growth
Control, one is used as negative control.
In above-mentioned 96 orifice plate, preceding 11 hole adds 108The CFU/mL μ L of bacteria suspension 0.5, make the final inoculum concentration be about
105CFU/mL.Add bacterium speed will as quickly as possible, in order to avoid overlong time, causes every hole bacterial growth Time Inconsistency and influence result
Judge.Each bacterial strain does 3 parallel tests simultaneously.Completed by the superclean bench alcolhol burner of whole process after sterilization.Carefully
Operation, prevents from polluting.96 orifice plates being inoculated with are put into 37 DEG C of constant incubator culture 16-20h, then observe and record knot
Fruit.
After the completion of culture, 96 orifice plates are taken out from insulating box, bacterial growth situation in peep hole.Result of determination it
Before, result is just significant when determining the bacterium normal growth in growth control hole, negative control hole without bacterial growth.Naked eyes are seen
Examine MIC of the drug concentration in the hole of no bacterial growth as the medicine to the bacterium.If there is hole phenomenon is jumped, then weight is needed
Retrial is verified.
The antibacterial activity test result of the episode compound of the present invention, is listed in table 9.Generally speaking, compound pair
S.aureus inhibitory activity is better than E.coli；To S.aureus bacterial strains, there is the MIC of 34 compounds<0.5 μ g/mL, there is 34
The μ g/mL of individual compound MIC=1~8；To E.coli bacterial strains, there is the MIC of 6 compounds<0.5 μ g/mL, separately there are 16 compounds
The μ g/mL of MIC=1~8.
Bioactivity result of the compound of table 9 to S.aureus and E.coli
3. Escherichia coli withhold the inhibitory activity measure of bacterium
The small subgroup that bacterium (Bacterial persister) is certain proportion phenotype alienation in some bacterial community is withheld,
Slow growth conditions or temporary sleep state is shown as, can tolerate the effect of lethasl concentration antibiotic.Not yet finding at present can be complete
The antibacterials and treatment means for withholding bacterium are removed, its appearance is that modern medicine study brings huge challenge.Research shows,
It is relevant with many microorganism problems to withhold bacterium, includes the multidrug resistance of bacterium infection, chronic infection and bacterial biof iotalm, therefore
It is the key means for treating these microorganism problems effectively to remove and withhold bacterium.The present invention is carried out with large intestine to partial target molecule
Bacillus is the anti-withholding bacterium activity research of research object, to obtain with the chemical small molecule for killing withholding bacterium ability.The present invention
The coli strain of use：The bacterial strains of Escherichia coli Escherichia coli ATCC 25922, it is Southwest University's life science
Modern biotechnology medicine research institute of institute conservation bacterial strain.
The preliminary screening of compound：Dissolved after compound is weighed on demand with DMSO.The Escherichia coli of conservation are pressed 1:100
It is seeded in sterilized LB culture mediums, is put into 37 DEG C of cultures of shaking table to mid-log phase (OD600=0.2), it is added dropwise per the μ L of hole 100
Into 96 orifice plates, final concentration of 100 μ g/mL ampicillin Amp is added per hole according to experimental design, under the concentration, is held
Stay bacterium model to be formed, final concentration of 30 μM of compound is then added per hole, and the bacterium solution for only adding DMSO is set as negative
Control.After 96 orifice plates are put into 37 DEG C of incubator culture 9h, 10 μ L bacterium solutions are taken to drip plate per hole, by solid LB plate incubated overnights,
Observe colony growth situation.
The compound of table 10 kills the experimental result that Escherichia coli withhold bacterium
Influence of the compound to bacterium under normal growth state：Choose 9 changes of display 75%~100% in primary dcreening operation result
Compound tests its killing action to bacterium under normal growth state：The Escherichia coli of conservation are pressed 1:100 are seeded to and have sterilized
LB culture mediums in, be put into the culture of 37 DEG C of shaking table to mid-log phase (OD600=0.2), it is added dropwise to per the μ L of hole 100 in 96 orifice plates, point
Final concentration of 30 μM of above-mentioned 9 compounds are not added, and are set and only added DMSO bacterium solution as negative control.By 96 orifice plates
After being put into 37 DEG C of incubator culture 9h, take 10 μ L bacterium solutions to drip plate per hole, by solid LB plate incubated overnights, observe colony growth feelings
Condition.And to bacterium solution gradient dilution (dilution gradient 10-1) drop plate, further look at colony growth situation.
If bacterium solution dilution 102Times, the presence of bacterium can not be found after progress Bacteria Culture, is shown added by bacterium solution correspondence
The sterilizing ability of compound is strong；If conversely, bacterium solution dilution 106Times, observed after culture with control group (DMSO) bacterium solution without obvious
Difference, then show its corresponding compound almost without sterilizing ability.
Test result indicates that in above-mentioned 9 have the compound of preferable inhibitory activity to Escherichia coli withholding bacterium, preparation example
6th, the compound of preparation example 22 and preparation example 24 not only has the ability killed and withhold bacterial strain, also there is the normal large intestine of stronger killing
The ability of bacillus；Though the compound of embodiment 4, preparation example 4 and preparation example 12 has the ability killed and withhold bacterial strain, kill normal
The ability of Escherichia coli is suitable with negative control, almost without bactericidal activity.
Influence experimental result of the compound of table 11 to bacterium under normal growth state
4. citrus pathogenic bacteria Antibacterial Activity
Citrus bacterial canker disease (citruscanker) is the great quarantine disease for influenceing world's Orange Producing, can cause harm tens
Kind rutaceae.The disease causes harm seriously to citrus nursery stock, treelet, causes to fall leaves, tree vigo(u)r decline；Also adult fruit tree can be made
As evil, a large amount of sheddings can be caused when serious, scab greatly reduces citrus fruit economic value.
The cause of disease of citrus brown spot is alternaric bacteria (Alternatia alternate), belongs to Deuteromycotina Hyphomycetes silk
Spore mesh dead color Cordycepps Alternaria, the susceptible rear blade of plant is easy to fall off, and the fallen leaves of ground can be used as primary source of infection, cause disease to pass
Broadcast sprawling.Conidium mainly on susceptible mature leaf surface, is propagated by wind-force, then rests on the young fruit or tender of sensitivity
Ye Shang.When damp condition meets, conidium sprouts quickly, starts to produce toxin, infects blade directly or by stomata.
Citrus processing Antibacterial Activity：Weigh 1mg compound samples to dissolve in 50 μ L DMSO, use ultra-pure water
550 μ L are settled to as sample mother liquor (1.82mg/mL).10 μ L mother liquors are taken to be used as sample in 1mL ultra-pure waters (0.02% tween)
Product solution a (0.0182mg/mL), then prepare sample solution b (0.0091mg/mL) successively using coubling dilution.
Under the ulcer bacteria for cultivating 3d in PDA culture medium is washed with 5mL LB fluid nutrient mediums, 195mL LB are added to
In fluid nutrient medium, vibration mixes standby.450 μ L citrus ulcer bacterias bacterium solutions and above-mentioned are separately added into each 2mL centrifuge tubes
The variant μ L of concentration (a, b) sample solution 50 so that sample ultimate density is respectively A (0.00182mg/ in each mixed bacteria liquid
ML), B (0.00091mg/mL), 28 DEG C, 200rmin-1OD is determined after constant-temperature shaking culture 14h600Under each mixed bacteria liquid OD values
And calculate inhibiting rate (inhibiting rate %=(ODBlank-ODSample)/ODBlank× 100%).Each processing repeats three times.
Test result indicates that compound of the invention has certain bacteriostatic activity to citrus processing, especially make
The inhibiting rate of standby example 6, preparation example 22, the compound of preparation example 23 and preparation example 24 under low concentration (0.00091mg/mL) is still super
80% is crossed, shows good DEVELOPMENT PROSPECT.
The target compound canker resistant germ Activity Results of table 12
Citrus brown patch germ Antibacterial Activity：7d foxiness will be cultivated in PDA culture medium with 0.05% Tween 80
Germ conidium is washed down, standby after four layers of sterile lens wiping paper filtering；1mg compound samples are weighed to dissolve in 50 μ L DMSO,
550 μ L are settled to as sample mother liquor (1.82mg/mL) by the use of ultra-pure water.2 μ L mother liquors are taken to make in 1mL PDA (0.02% tween)
For sample solution a (0.00364mg/mL), sample solution b (0.00182mg/mL) is prepared successively using coubling dilution.And in
48 orifice plates add 0.5mL sample solutions and 1.5mLPDA culture mediums in every hole so that test final concentration is respectively A
After (0.000910mg/mL) and B (0.000455mg/mL), 2 μ L conidial suspensions are inoculated with, are surveyed after 28 DEG C of illumination cultivation 3d
Measure colony diameter.Using the bacterium colony being seeded in the PDA culture medium for being not added with sample solution as blank control, different samples are calculated to disease
Inhibiting rate (inhibiting rate %=(the colony diameters of fungal pathogensesBlank- colony diameterSample)/colony diameterBlank× 100%).
Test result indicates that test concentrations 0.000910mg/mL, the relative inhibition for having 24 compounds exceedes
20%；Test concentrations reduce by one times, and the relative inhibition of also 5 compounds is more than 20%, it is shown that certain potentiality to be exploited.
The anti-citrus brown patch germ Activity Results of the target compound of table 13
Tumor targets NNMT 5. (hNNMT) inhibitory activity determines
NNMT (Nicotinamide N-methyltransferase, NNMT) is to utilize egg in recent years
Filtered out by Bai Zuxue and the more different cancerous tissues of biochip technology and cancer between (or normal) tissue during differential expression molecule
The protease of unconventionality expression in tumor tissues.Its differential expression in kinds of tumors tissue, and study and find it with swelling
The various features sexual biology function such as tumor cell proliferation, transfer and resistance to chemicotherapy is closely related, prompts NNMT to be used as potential
The mark of tumour auxiliary diagnosis, individuation and targeted therapy.
The inhibitory activity measure of hNNMT target spots：By detecting product MNAN (the Methyl n- in hNNMT expression paths
Amyl nitrosamine) and 10 μM of SAH (S-adenosyl homocysteine) single concentration (SP) inhibitory activity tests and
More concentration (CRC) inhibitory activity are tested to represent inhibitory activity of the target compound to hNNMT target spots.
Pass throughDetermine the inhibitory activity of target compound, using liquid chromatography/mass spectrometry method (LC/MS) and Luminescent Cell Viability Assay test more concentration test samples to HEK293 cells
Half-inhibition concentration IC50。
Activity data is shown, when test concentrations are 10 μM, hNNMT MNAN SP inhibitory activity is more than 10% compound
There are 9, the compound inhibitory activity of embodiment 66 is best, and hNNMT MNAN SP and hNNMT SAH SP inhibiting rate is respectively
74.2% and 71.2%, IC50Value is respectively 90.0 μM and 118.9 μM.
The inhibitory activity result (10 μM) of table 14hNNMT target spots
HNNMT target spots relative inhibition (the Rel IC of the compound of 15 embodiment of table 6650)
6. interleukins IL-17PPI inhibitory activity determines
IL-17 is a kind of mainly proinflammatory cytokine as caused by the T cell activated, can promote T cell activation and
Stimulate epithelial cell, endothelial cell, fibroblast to produce cytokine profiles such as IL-6, IL-8, granulocytes-macrophages to pierce
Swash the factor (GM-CSF) and chemokines and (the Cellular adhesion molecule 1, CAM- of cell adhesion molecule 1
1) generation of inflammation, is caused.IL-17 is the early stage startup factor of the inflammatory reaction of induced t cell, can be by promoting before discharging
Inflammatory cytokine amplifies inflammatory reaction.After IL-17 is combined with acceptor, map kinase approach and expression of nuclear factor kappa B can be passed through
(Nuclear factor κ B, NF- κ B) approach plays its biological action.IL-17 can be mediated effectively caused by Th17 cells
The excited process that neutrophil leucocyte is mobilized, so that the effectively inflammatory reaction of mediating tissue.
Inhibitory activity assay method of the target compound to IL-17：Cell is stimulated to lead to the genetic recombination IL-17A of culture
Single concentration (SP) the inhibitory activity test of 100 μM of target compound and the test of more concentration (CRC) inhibitory activity are crossed, is passed throughDetermine the IL-17 inhibitory activity of target compound.
Activity Results are shown：Test concentrations are 100 μM, and compound of the inhibiting rate more than 20% has 7, wherein embodiment 66
Compound inhibitory activity it is best, be 52.4%.
The IL17PPI inhibitory activity result (100 μM) of the target compound of table 16
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with
The present invention is described in detail good embodiment, it will be understood by those within the art that, can be to the skill of the present invention
Art scheme is modified or equivalent substitution, and without departing from the objective and scope of technical solution of the present invention, it all should cover at this
Among the right of invention.
Claims (10)
1. compound of formula I, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt：
Wherein X is selected from：C1-C6 alkyl；C3-C6 cycloalkyl；Substituted or unsubstituted C6-C10 aryl, taking on the aryl
Dai Jiwei is one or more, is independently selected from：Halogen；Amino；Hydroxyl；C1-C6 alkyl；C3-C6 cycloalkyl；
Z is selected from：N or C-R7；R7Selected from H；C1-C6 alkoxy or halogens；
R1And R2It is each independently selected from：H；C1-C6 alkyl；C1-C6 haloalkyls；C1-C6 alkoxies；C1-C6 alkyl amino；
Halogen；Hydroxyl；Amino or cyano group；
R3、R4The substituted or unsubstituted 5-7 members saturated heterocyclic at least containing 1 N atom is collectively forming with the group being connected,
Substituent on the saturated heterocyclic is one or more, is independently selected from：Halogen；Amino；Hydroxyl；C1-C6 alkyl；C3-C6 rings
Alkyl；R5Selected from H, C1-C6 alkyl；
Or R3、R5The 5-7 member saturated heterocyclics containing 2 N atoms are collectively forming with the group being connected；R4It is selected from：H, halogen；
Amino；Hydroxyl；C1-C6 alkyl；
A is selected fromCarboxyl or halogen；
Het is the 5-7 member hetero-aromatic rings containing at least one nitrogen-atoms；R6Selected from H, C1-C6 alkyl；
N, k is respectively 0 to 3 integer.
2. compound shown in Formula II, formula III, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their medicine
Learn acceptable salt：
Wherein X is selected from：C1-C6 alkyl；C3-C6 cycloalkyl；Substituted or unsubstituted C6-C10 aryl, taking on the aryl
Dai Jiwei is one or more, is independently selected from：Halogen；Amino；Hydroxyl；C1-C6 alkyl；C3-C6 cycloalkyl；
Z is selected from：N or C-R7；R7Selected from H；C1-C6 alkoxy or halogens；
R1And R2It is each independently selected from：H；C1-C6 alkyl；C1-C6 haloalkyls；C1-C6 alkoxies；Halogen；Hydroxyl；C1-C6's
Alkyl amino；Amino or cyano group；
R4It is selected from：H, halogen；Amino；Hydroxyl；C1-C6 alkyl；
R5Selected from H, C1-C6 alkyl；
A is selected fromOr halogen；
Het is the 5-7 member hetero-aromatic rings containing at least one nitrogen-atoms；R6Selected from H, C1-C6 alkyl；
N, k is respectively 0 to 3 integer；
M is 1 or 2.
3. compound as claimed in claim 2, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their medicine
Learn acceptable salt：
Wherein, A is selected from following structure：
4. formula IV, Formula V, Formula IV, Formula VII, Formula VIII and compound shown in Formula IX, its raceme, stereoisomer, tautomerism
Body, nitrogen oxides or their pharmaceutically acceptable salt：
X is selected from：Methyl；Ethyl；Propyl group；Butyl；Cyclopropyl；The substituted or unsubstituted phenyl of halogen；
Z is selected from：N or C-R7；R7Selected from H；Methoxyl group；Ethyoxyl；Fluorine or chlorine；
Wherein R1And R2It is each independently selected from：H；Methyl；Ethyl；Trifluoromethyl；Methoxyl group；Ethyoxyl；Halogen；Hydroxyl or amino；
R4It is selected from：H, halogen；Amino；Hydroxyl；Methyl or ethyl；
R5Selected from H；Methyl or ethyl；
A is selected from
N is 1 or 2 or 3；
M is 1 or 2.
5. compound as follows, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmacy can
Receive salt：
6. any compound, its raceme, stereoisomer, tautomerism in a kind of pharmaceutical composition, including claim 1-5
Body, nitrogen oxides or their pharmaceutically acceptable salt.
7. pharmaceutical composition as claimed in claim 6, it is characterised in that described pharmaceutical composition also includes：A) it is pharmaceutically acceptable
Carrier and/or auxiliary agent；And/or b) one or more suitable other active components.
8. compound, its raceme, stereoisomer, dynamic isomer, nitrogen as described in any claim in claim 1-5
The purposes of oxide or their pharmaceutically acceptable salt in the medicine for preparing treatment disease, the disease are selected from bacterium and its held
Stay bacterium infection associated diseases, citrus pathogenic infection associated diseases, inflammatory disease or tumour.
9. purposes as claimed in claim 8, the bacterium includes mycobacterium tuberculosis, staphylococcus aureus, Escherichia coli, sand
Door bacterium pseudomonas aeruginosa；The citrus pathogenic bacteria are selected from：Citrus processing；Citrus brown patch germ or citrus green mold bacterium；Institute
Inflammatory disease is stated as inflammatory disease related IL-17, preferably rheumatoid arthritis (RA), asthma, multiple sclerosis (MS),
Chronic obstructive pulmonary disease (COPD), ARDS (ARDS), idiopathic pulmonary fibrosis (IPF), inflammmatory intestinal disease
Sick (IBD), Crohn's disease, uveitis, macular degeneration, colitis, psoriasis, Wallerian degeneration, antiphospholipid antibody syndrome
(APS), acute coronary syndrome, ISR, atherosclerosis, relapsing polychondritis (RP), acute or chronic hepatitis,
Plastic surgery implantation, glomerulonephritis, lupus and the autoimmune disease of failure；The tumour is selected from：Lung cancer, kidney,
Carcinoma of the colon and rectum, nasopharyngeal carcinoma, breast cancer, cancer of pancreas, liver cancer, stomach cancer, glioma, carcinoma of urinary bladder, with OSCC or
Medulloblastoma.
10. prepared by compound, stereoisomer or its pharmaceutically acceptable salt as described in any claim in claim 1-5
Application in tumour diagnostic reagent.
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| CN201711102862.5A CN107880023B (en) | 2017-11-10 | 2017-11-10 | Fluoroquinolone amino derivative and application thereof |
| CN201911252190.5A CN111087390B (en) | 2017-11-10 | 2017-11-10 | Fluoroquinolone amino derivative and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864043A (en) * | 2018-09-18 | 2018-11-23 | 中国医学科学院生物医学工程研究所 | A kind of preparation method and purposes of novel quinolone compounds |
| CN109096278A (en) * | 2018-09-26 | 2018-12-28 | 西南大学 | Fluoquinolone-nitrogen azoles hybrid derivatives, preparation method and its usage |
| WO2020036154A1 (en) * | 2018-08-13 | 2020-02-20 | Otsuka Pharmaceutical Co., Ltd. | Novel medicament for treating inflammatory bowel disease |
| CN112159390A (en) * | 2020-09-25 | 2021-01-01 | 西南大学 | Synephrine fluoroquinolone derivative and preparation method and application thereof |
| CN112159355A (en) * | 2020-09-25 | 2021-01-01 | 西南大学 | Fluoroquinolone p-aminosalicylate derivative and intermediate, preparation method and application thereof |
| CN113480519A (en) * | 2021-07-23 | 2021-10-08 | 西南大学 | Oxacycloxacin derivative and preparation method and application thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1683339A (en) * | 2005-02-22 | 2005-10-19 | 南京澳新医药科技有限公司 | 7-substituted-8-methoxy fluoroquinolone carboxylic derivatives, preparing process, preparation and use thereof |
| WO2017017631A2 (en) * | 2015-07-28 | 2017-02-02 | Vyome Biosciences Pvt. Ltd. | Antibacterial therapeutics and prophylactics |
| CN107721924A (en) * | 2017-11-10 | 2018-02-23 | 西南大学 | Gatifloxacin derivative and its production and use |
| CN107827815A (en) * | 2017-11-10 | 2018-03-23 | 西南大学 | Fluoroquinolones aminoderivative and its purposes for preventing and treating citrus disease |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7632944B2 (en) * | 2007-01-24 | 2009-12-15 | Bausch & Lomb Incorporated | Quinolone carboxylic acids, derivatives thereof, and methods of making and using same |
| GB0705915D0 (en) * | 2007-03-28 | 2007-05-09 | Helperby Therapeutics Ltd | New use |
| CN102827187B (en) * | 2012-07-18 | 2014-05-14 | 河南大学 | Fluoroquinolone acetal isoniazone, and preparation method and application thereof |
| CN102993170A (en) * | 2012-11-23 | 2013-03-27 | 西南大学 | Clinafloxacin derivative as well as preparation method and application thereof |
| CN103396396B (en) * | 2013-08-12 | 2015-09-09 | 西南大学 | Amido alkane acyl Clinafloxacin and application thereof |
| CN103405435B (en) * | 2013-08-30 | 2014-12-10 | 西南大学 | Application of clinafloxacin amino derivatives and medicinal salts thereof in preparing antitubercular medicaments |
| CN107459507B (en) * | 2016-06-03 | 2021-02-19 | 西南大学 | Clinafloxacin oxazolidinyl derivative and preparation method and application thereof |
-
2017
- 2017-11-10 CN CN201911252190.5A patent/CN111087390B/en active Active
- 2017-11-10 CN CN201711102862.5A patent/CN107880023B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1683339A (en) * | 2005-02-22 | 2005-10-19 | 南京澳新医药科技有限公司 | 7-substituted-8-methoxy fluoroquinolone carboxylic derivatives, preparing process, preparation and use thereof |
| WO2017017631A2 (en) * | 2015-07-28 | 2017-02-02 | Vyome Biosciences Pvt. Ltd. | Antibacterial therapeutics and prophylactics |
| CN107721924A (en) * | 2017-11-10 | 2018-02-23 | 西南大学 | Gatifloxacin derivative and its production and use |
| CN107827815A (en) * | 2017-11-10 | 2018-03-23 | 西南大学 | Fluoroquinolones aminoderivative and its purposes for preventing and treating citrus disease |
Non-Patent Citations (9)
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020036154A1 (en) * | 2018-08-13 | 2020-02-20 | Otsuka Pharmaceutical Co., Ltd. | Novel medicament for treating inflammatory bowel disease |
| CN108864043A (en) * | 2018-09-18 | 2018-11-23 | 中国医学科学院生物医学工程研究所 | A kind of preparation method and purposes of novel quinolone compounds |
| CN109096278A (en) * | 2018-09-26 | 2018-12-28 | 西南大学 | Fluoquinolone-nitrogen azoles hybrid derivatives, preparation method and its usage |
| CN109096278B (en) * | 2018-09-26 | 2021-05-28 | 西南大学 | Fluoroquinolone-azole hybrid derivative, preparation method and application thereof |
| CN112159390A (en) * | 2020-09-25 | 2021-01-01 | 西南大学 | Synephrine fluoroquinolone derivative and preparation method and application thereof |
| CN112159355A (en) * | 2020-09-25 | 2021-01-01 | 西南大学 | Fluoroquinolone p-aminosalicylate derivative and intermediate, preparation method and application thereof |
| CN112159355B (en) * | 2020-09-25 | 2022-06-24 | 西南大学 | Fluoroquinolone p-aminosalicylate derivative and intermediate, preparation method and application thereof |
| CN112159390B (en) * | 2020-09-25 | 2022-07-19 | 西南大学 | Synephrine fluoroquinolone derivative and preparation method and application thereof |
| CN113480519A (en) * | 2021-07-23 | 2021-10-08 | 西南大学 | Oxacycloxacin derivative and preparation method and application thereof |
| CN113907079A (en) * | 2021-11-10 | 2022-01-11 | 西南大学 | Application of chloralkanoyl fluoroquinolone in preparing medicine for preventing and treating citrus canker |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107880023B (en) | 2021-02-19 |
| CN111087390B (en) | 2022-07-05 |
| CN111087390A (en) | 2020-05-01 |
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