CN106220562B - The new application of two kinds of quinoline ring class drugs - Google Patents
The new application of two kinds of quinoline ring class drugs Download PDFInfo
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- CN106220562B CN106220562B CN201610617423.7A CN201610617423A CN106220562B CN 106220562 B CN106220562 B CN 106220562B CN 201610617423 A CN201610617423 A CN 201610617423A CN 106220562 B CN106220562 B CN 106220562B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides the new applications of quinoline ring class drug.Specifically, the present invention provides the purposes of compound shown in formula A or its optical isomer or its racemic modification or its solvate or its pharmaceutically acceptable salt, they be used to prepare a pharmaceutical composition or preparation, and described pharmaceutical composition or preparation are for (a) inhibition transient receptor potential channel protein TRPA1；(b) relevant to transient receptor potential channel protein disease is treated, in formula, each group definition is as noted in the discussion.
Description
Technical field
The present invention relates to field of medicinal chemistry, relates more specifically to quinoline ring class drug and it is inhibiting transient receptor potential
Application in terms of channel protein TRPA1.
Background technique
Transient receptor potential channel (Transient receptor potential, TRP) is that one kind is present in cell membrane
On important cationic channel constitute superfamily protein, for the first time by Minke etc. when studying drosophila visual transduction system
It was found that.Subsequent research has found a series of TRP families channel member again.It is logical according to about 30 kinds of TRP found in mammality
The sequence homology in road is divided into altogether 6 subfamilies, i.e. TRPC, TRPV, TRPM, TRPML, TRPA and TRPP.The channel TRP
C-terminal and N-terminal be respectively positioned in cell membrane, and 6 containing S1-S6 transmembrane domains.Wherein ligand knot on structural domain S1-S4
The reaction site of conjunction may be by gate aperture, but lack positive charge amino acid residue as valtage-gated logical in S4 structural domain
Road, most of TRP have very weak voltage sensitivity, lack selection index system (PCa/PNa ratio is less than 10).S5-S6 cross-film
Structural domain hydrophilic area forms duct, and constitutes a low gate in the intracytoplasmic end S6 monocycle, it can be by opening
It closes regulation cation and enters channel.
Letter " A " in TRPA1 refers to ankyrin (Ankyrin), it be able to be distinguished out in TRP family be by
In at least existing ankyrin repeat of the N-terminal of TRPA1 be 14, higher than 3~4 repetitions of other subfamilies.2 spirals
Calcium binding motif structural domain be present in the N-terminal of TRPA1, but the effect of structural domain is unclear.In addition to the critical function of N-terminal,
It is found that the electric current of TRPA1 can be greatly reduced in the mutation of the C-terminal single amino acids of TRPA1.It is newest studies have shown that a position
Acquired function mutation in the transmembrane structure S4 of TRPA1 will lead to the pain syndrome of familial onset, this discovery provides
First case pain relevant TRP ion channel disease.
Activate the channel TRPA1 there are many approach, the channel TPR can generally be activated by phospholipase C, and g protein coupled receptor exists
It is acted in the activation of TRPA1；In ligand activation approach, a series of chemical stimulation can activate TRPA1, be reported
The agonist in road include: cinnaldehydrum (cortex cinnamomi), allicin and diallyl disulfide (garlic), isothiocyanic acid salt (mustard oil, wasabi,
Horseradish), methacrylaldehyde (cigarette), 9- tetrahydrocannabinol (hemp), diallyl disulfide, mustard oil (mustard), icilin, water
Poplar acid methyl esters (wintergreen) etc..There is document to report recently, agonist of the peppermint as TRPM8 has double-hump effect to TRPA1:
Inhibit TRPA1 at high concentrations, when low concentration activates TRPA1.In addition to exogenous agonistic agent, recent studies have shown that TRPA1 can
With the endogenous compound 4- hydroxyl nonenoic acid discharged during tissue damage, inflammation, oxidative stress and deoxidation -12 15-,
14 prostaglandin J2 activation.It is newest the study found that agonist passes through half Guang of N-terminal with TPRA1 in the activation of TRPA1
Histidine residue covalent interaction activates TRPA1.In addition to both the above biochemistry activated pathway, the channel TRPA1 can also be hurt
Evil property low temperature and mechanical stimulus activation.
Summary of the invention
The purpose of the present invention is to provide a kind of active compound of inhibition transient receptor potential channel protein TRPA1 and its
Using.
In the first aspect of the present invention, a kind of compound shown in formula A or its optical isomer or its racemic are provided
The purposes of body or its solvate or its pharmaceutically acceptable salt, which is characterized in that be used to prepare pharmaceutical composition or system
Agent, described pharmaceutical composition or preparation inhibit transient receptor potential channel protein TRPA1 for (a)；(b) treatment and transient receptor
The relevant disease of current potential channel protein；
In formula,
X1 indicate without or 1 or 2 substituent group selected from the group below: halogen ,-OH, substituted or unsubstituted C1-C8Alkyl takes
Generation or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C1-C8Alkoxy or substituted or unsubstituted C3-C8Cycloalkanes oxygen
Base, wherein the substitution, which refers to, has one or more substituent groups selected from the group below: halogen ,-OH ,-NH2、-CN、-NH(C1-C3
Alkyl) ,-N (C1-C3Alkyl)2；
X2 indicate without or 1,2 or 3 substituent group selected from the group below: substituted or unsubstituted C1-C8Alkoxy, substitution or
Unsubstituted C3-C8Cycloalkyloxy or halogen, wherein the substitution, which refers to, has one or more substituent groups selected from the group below: halogen
Element ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
R1 is-L-Z group,
Wherein L is selected from the group :-C (O)-NRc-Ym- (C1-C4Alkylidene)-,-NRc-Ym- (C1-C4Alkylidene)-, wherein Y
For substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C4-C10Heteroaryl, the heteroaryl contain 1-3 selected from N,
O, the hetero atom of S；M is 0 or 1, wherein the substitution, which refers to, has one or more substituent groups selected from the group below: halogen ,-OH,
C1- C3Alkyl, C1-C3Halogenated alkyl ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
Rc is selected from: H, C1-C6Alkyl or C1-C6Halogenated alkyl or C3-C6Naphthenic base；
Z isRa and Rb are each independently selected from: H, C1-C6Alkyl or C1-C6Halogenated alkyl or C3-C6Cycloalkanes
Base.
In another preferred example, Ra and Rb are each independently selected from: C1-C6Alkyl or C1-C6Halogenated alkyl.
In another preferred example, the formula A compound has structural formula A1:
In formula,
R1 is as defined above；
R2 is substituted or unsubstituted C1-C8Alkoxy or substituted or unsubstituted C3-C8Cycloalkyloxy；Wherein, described
Substitution refer to that there are one or more substituent groups selected from the group below: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-
C3Alkyl)2；
R3 is H, substituted or unsubstituted C1-C8Alkoxy or halogen, wherein the substitution, which refers to, has one or more
Substituent group selected from the group below: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2。
In another preferred example, Ra and Rb are each independently selected from: C1-C6Alkyl or C1-C6Halogenated alkyl.
In another preferred example, m=0.
In another preferred example, m=1, and the substituted or unsubstituted phenyl of Y=.
In another preferred example, Ra=Rb=C2Alkyl.
In another preferred example, Rc=H.
In another preferred example, R2=-O- (C4Alkyl).
In another preferred example, R3=H or Cl.
In another preferred example, the R1 is selected from:
In another preferred example, the A formula compound includes following compound or its pharmaceutically acceptable salt:
In another preferred example, the formula A compound is selected from the group:
In another preferred example, the transient receptor potential channel protein TRPA1 is people's transient receptor potential channel egg
White TRPA1.
In another preferred example, the disease relevant to transient receptor potential channel protein is selected from the group: pain, inflammation
Disease, respiratory disorder, itch, urinary-tract disorders, inflammatory bowel disease.
In another preferred example, the respiratory disorder is selected from the group: asthma, cough, Chronic Obstructive tuberculosis.
In another preferred example, contain 0.001-99wt% in the pharmaceutical composition described pharmaceutical composition, preferably
The formula A compound or its optical isomer of ground 0.1-90wt%, more preferably 1-80wt% or its racemic modification or its solvation
Object or its pharmaceutically acceptable salt, are based on the total weight of the composition.
In another preferred example, the pharmaceutical composition or preparation can also containing other drugs active constituent or pharmaceutically
Acceptable carrier.
In the second aspect of the present invention, which is characterized in that contain 1 compound of (a) formula or its pharmaceutically acceptable salt, and
Its optical isomer or its pharmaceutically acceptable salt；(b) 2 compound of formula or its pharmaceutically acceptable salt and its optics are different
Structure body or its pharmaceutically acceptable salt；And (c) pharmaceutically acceptable carrier,
In another preferred example, when the active constituent contains there are two types of organizing timesharing, the weight ratios of two kinds of components be 1:20 extremely
20:1, preferably 1:10 to 10:1, more preferably 1:5 to 5:1.
In another preferred example, in the pharmaceutical composition, the total amount of component (a) is 0.001-99wt%, preferably
Ground 0.1-90wt%, more preferably 1-80wt%, are based on the total weight of the composition.
In another preferred example, the pharmaceutical composition or preparation can also containing other drugs active constituent or pharmaceutically
Acceptable carrier.
In the third aspect of the present invention, a kind of medicine box is provided, which is characterized in that the medicine box includes:
(1) the first container, and the first pharmaceutical composition in the container, first pharmaceutical composition contain
There are 1 compound of formula or its pharmaceutically acceptable salt and its optical isomer or its pharmaceutically acceptable salt, and pharmaceutically
Acceptable carrier；
(2) second container, and the second pharmaceutical composition in the container, second pharmaceutical composition contain
There are 2 compound of formula or its pharmaceutically acceptable salt and its optical isomer or its pharmaceutically acceptable salt；And pharmaceutically
Acceptable carrier；
And the operation instructions that (3) are optional.
In the fourth aspect of the present invention, a kind of inhibition transient receptor potential channel protein of external non-therapeutic is provided
The active method of TRPA1, which is characterized in that by transient receptor potential channel protein and formula A compound or its optical isomer or
Its racemic modification or its solvate or its pharmaceutically acceptable salt are contacted, to inhibit transient receptor potential channel
The activity of albumen, wherein the formula A compound is as described in first aspect present invention.
In the fifth aspect of the invention, a kind of method for inhibiting transient receptor potential channel protein TRPA1 is provided,
Characterized in that it comprises the following steps: formula A compound is applied to the object needed, wherein the formula A compound such as present invention first
Described in aspect.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 is that amodiaquine hydrochloride (1) inhibits the active amount effect relation curve figure of TRPA1.
Specific embodiment
The present inventor has unexpectedly discovered class formation compound as shown in formula A by depth studying extensively for the first time
It can inhibit the activity of TRPA1 significantly.Experiment shows that the formula A compound has preferable inhibitory effect to TRPA1, this
The formula A compound of invention can be used for treating relevant to TRPA1 target spot pain, inflammation, respiratory disorder, related with oxidative stress
Itch, urinary-tract disorders, inflammatory bowel disease etc..On this basis, the present invention is completed.
Term
Term " C1~C8Alkoxy " refers to the linear or branched alkyl group with 1~8 carbon atom, such as methoxyl group, ethoxy
Base, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
Term " C1~C8Alkyl " refers to the linear or branched alkyl group with 1~8 carbon atom, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl or similar group.
Term " C3~C8Naphthenic base " refers to the naphthenic base with 3~8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopenta,
Suberyl or similar group.
Term " C2~C6Alkenyl " refers to the alkenyl with 1~6 carbon atom, such as vinyl, acrylic, isopropenyl, fourth
Alkenyl, isobutenyl, secondary cyclobutenyl, tertiary cyclobutenyl or similar group.
Term " 5-7 circle heterocyclic ring ", which refers to, has one or more, and preferably 1-3 heteroatomic cyclic structures, the ring can
To be saturated or unsaturated ring.
Term " halogen " refers to F, Cl, Br and I.
Term " C6-C10Aryl " refers to the cyclic group with aromatic structure, such as phenyl, naphthalene.
Term " C4-C10Heteroaryl " refers to that one or more carbon atoms are formed by cyclic group after being exchanged for heteroatoms in aryl
Group, wherein hetero atom is selected from N, O or S.The example of heteroaryl includes (but being not limited to): pyridyl group, pyridazinyl, pyrimidine radicals, pyrrole
Piperazine base.
Active constituent
As used herein, " the compounds of this invention ", " quinoline ring class drug of the invention and its derivative " or " formula A chemical combination
Object " is used interchangeably, and refers to compound shown in formula A or its raceme, corresponding isomers or its pharmaceutically acceptable salt.It answers
Understand, which further includes the mixture of said components.
The compounds of this invention is not only inhibited to TRPA1, also has certain inhibition to other members in TRP family
Effect.
In formula, each group is as defined above.
It in the present invention, further include the pharmaceutically acceptable salt of formula A compound.Term " pharmaceutically acceptable salt " refers to
The compounds of this invention and acid or alkali are formed by the salt for being suitable as drug.Pharmaceutically acceptable salt includes inorganic salts and organic
Salt.A kind of preferred salt is the salt that the compounds of this invention and acid are formed.The acid for suitably forming salt includes but is not limited to: hydrochloric acid,
The inorganic acids such as hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, rich horse
Acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；With
And the acidic amino acids such as aspartic acid, glutamic acid.
Formula A compound of the invention can be used method well known to those skilled in the art in the prior art and be prepared, right
The response parameter of each step is not particularly limited.In addition, typical compound of the invention can also be obtained by commercially available mode.
As used herein, in formula A compound, if there is asymmetric carbon atom, then asymmetric carbon atom can be R configuration,
May be S configuration, or both mixture.
Camoquin is aminoquinolines antimalarial, and Antimalarial is similar to chloroquine, acts on erythrocyte stage malaria
Protozoon can control rapidly clinical symptoms.In addition to this, the plasmodium for also fighting chloroquine is also effective.Adverse reaction is less, there is head
Dizzy, vomiting and diarrhea etc..It can be used for pregnant woman, children and the bad person of liver function.
Hydrochloric acid stage cacaine is anesthesia similar drug, and in the local anaesthetics of clinical application, stage cacaine is to act on most strong, toxicity
Maximum, longest one kind of holding time.The anesthetic potency of drug administration by injection is 15 times of procaine, and toxicity is also 15 times big.It works
It is relatively slow, about 15min, but the continuous action time is 3 times of procaine.Local irritation is small, and penetration power is stronger.For surface fiber crops
Liquor-saturated, infiltration anesthesia or peridural anesthesia.
Transient receptor potential channel protein (TRPA1)
Transient receptor potential channel protein (Transient receptor potential, TRPA1) is that one kind is present in
The superfamily protein that important cationic channel on cell membrane is constituted.The study found that the channel TRPA1 and pain, neuropathy etc.
Disease is related.In addition, it is verified that, TRPA1 still treats inflammation, respiratory disorder, itch related with oxidative stress, urinary tract
The target of infection and inflammatory bowel disease.
In general, TRPA1 gene can be obtained with conventional method (such as PCR or fully synthetic), it is then connected into conventional expression vector
(such as pcDNA5, pcDNA3).Then, by the expression vector be transferred to suitable host cell (such as yeast cells, Chinese hamster ovary celI,
293 cells, Escherichia coli etc.), to obtain the cell strain of expression TRPA1.The cell strain of the expression TRPA1 can be used directly
In test, the TRPA1 isolated can also be used to test.
In the present invention, TRPA1 includes people and non-human mammal (such as rodent such as mouse and rat) source
TRPA1。
Purposes
The present invention also provides a kind of method for inhibiting transient receptor potential channel protein TRPA1, and treatment with it is instantaneous
The method of the relevant disease of receptor potential channel protein.
Above-mentioned formula A compound of the invention can be used for inhibiting TRPA1, and then prevention or treatment and transient receptor potential channel
The relevant disease of albumen.
In the present invention, the example of disease relevant to transient receptor potential channel protein includes (but being not limited to): pain
Bitterly, inflammation, respiratory disorder, itch, urinary-tract disorders, inflammatory bowel disease.Preferably, the respiratory disorder is selected from the group: asthma,
Cough, Chronic Obstructive tuberculosis.
In one embodiment, the present invention provides a kind of inhibition transient receptor potential channel proteins of external non-therapeutic
The active method of TRPA1, comprising: for example in vitro in cultivating system, by transient receptor potential channel protein or the expression egg
White cell and formula A compound (or its optical isomer or its racemic modification or its solvate or its is pharmaceutically acceptable
Salt) contacted, to inhibit the activity of transient receptor potential channel protein.
The present invention also provides a kind of methods for inhibiting transient receptor potential channel protein TRPA1, and this method, which can be, to be controlled
It is the property treated or non-therapeutic.In general, the method comprising the steps of: applying formula A compound of the invention to the object of needs.
Preferably, the object includes people and non-human mammal (rodent, rabbit, monkey, domestic animal, dog, cat etc.).
Composition and method of administration
The present invention provides a kind of for inhibiting the composition of transient receptor potential channel protein TRPA1.The combination
Object includes (but being not limited to): pharmaceutical composition, food compositions, dietary supplements, beverage composition for treating dental erosion etc..
In the present invention, the pharmaceutical composition can be directly used for disease treatment, for example, controlling for respiratory disorder
It treats.
The present invention also provides a kind of pharmaceutical composition, it contains the compounds of this invention and pharmaceutically of safe and effective amount
Acceptable carrier or excipient.This kind of carrier includes (but being not limited to): salt water, buffer, glucose, water, glycerol, second
Alcohol, pulvis, and combinations thereof.Pharmaceutical preparation should match with administration mode.
By taking pharmaceutical composition as an example, composition of the invention can be made into injection form, such as with physiological saline or contain
There are glucose and the aqueous solution of other adjuvants to be prepared by conventional method.The pharmaceutical composition of such as tablet and capsule etc
Object can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule preferably aseptically manufacture.
Pharmaceutical composition of the invention can also be made into pulvis for Neulized inhalation.
The dosage of active constituent is therapeutically effective amount, such as about 5 mg/kg body of about 1 microgram/kg body weight-daily
Weight.In addition, transient receptor potential channel protein TRPA1 inhibitor of the invention can be also used together with other therapeutic agents.
For pharmaceutical composition of the invention, required object (such as people and the inhuman food in one's mouth can be applied to by way of conventional
Newborn animal).Representative method of application includes (but being not limited to): oral, injection, Neulized inhalation etc..
It is by the medicament administration of safe and effective amount in mammal when using pharmaceutical composition, the wherein safe and effective amount
Typically at least about 10 micrograms/kg body weight, and in most cases no more than about 8 mg/kg weight, the preferably agent
Amount is about 1 mg/kg weight of about 10 micrograms/kg body weight-.Certainly, specific dosage is also contemplated that administration route, patient health
The factors such as situation, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include:
(a) formula A compound of the invention has preferable inhibitory effect to TRPA1.
(b) typical form A compound of the invention has excellent safety, toxic side effect very little or almost non-toxic secondary work
With.
(c) formula A compound of the invention mediates TRPA1 pain, inflammation have better treatment potential.
(d) formula A compound of the invention has been used for the treatment of human diseases by supervision department's approval, so the new application
Discovery can rapidly enter the clinical II phase and test, be conducive to shorten the research and development time and reduce R & D Cost.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor
Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.Unless otherwise stated, no
Then percentage and number are calculated by weight.
Material
Compound 1,2 is commercially available following compound:
Universal method
Test experiments of the compound of the present invention (1-2) to the inhibitory activity of transient receptor potential channel protein TRPA1
The test method of patch-clamp detection is automated by IonWorks Barracuda (IWB): stablizing expression mTRPA1
HEK293 cell, with contain 15g/mL Blasticidin S HCl, 200g/mL Hygromycin B and 10%FBS serum
DMEM culture medium, be placed in the culture bottle of T175, be put into 37 DEG C, 5%CO2Incubator in cultivate, to cell density grow
When to~80%, culture solution is removed, is rinsed one time with the phosphate buffer (PBS) of no calcium and magnesium, the Trypsin digestion 2 of 3mL is added
Minute, 7mL culture solution is added and terminates digestion.Cell is collected into the centrifuge tube of 15mL with 800 rev/min centrifugation 3 minutes,
The extracellular fluid that proper volume is added in cell is resuspended after removing supernatant, makes cell density control in 2-3 × 106/ mL is used in combination
It is tested in IWB.Extracellular fluid formula (in mM): 140NaCl, 5KCl, 1MgCl2,10HEPES,0.5EGTA,10Glucose
(pH 7.4)；Intracellular fluid formula (in mM): 140CsCl, 10HEPES, 5EGTA, 0.1CaCl2,1MgCl2(pH 7.2).Two
Property mycin B and experimental day, at 28mg/mL, then are configured to intracellular fluid the final concentration of 0.1mg/mL with DMSO Fresh.
IWB experiment uses population patch clamp (PPC) plate, and whole detection process are automatically performed by instrument,
Extracellular fluid is added in 384 holes of PPC plate, and is after intracellular fluid is added in plenum, to be added 6 μ L's under PPC plate
Cell liquid carries out sealing-in test, finally changes the intracellular fluid in plenum into intracellular fluid containing amphotericin B, makes sealing-in
Whole-cell recording technique pattern is formed after cell perforation.The sample frequency for recording TPRA1 electric current is 10kHz, and cell is clamped down in 0mV, electricity
Pressure stimulation order (channel protocol) is slope (ramp) voltage of a 300ms from -100mV to+100mV, every 10s
The stimulation of this voltage is given, mTRPA electric current is induced by 300M AITC.
Data record and current amplitude measurement export are by the completion of IWB software (version 2.5.3, Molecular
Devices Corporation, Union City, CA).Hole of the sealing-in impedance lower than 20M Ω will not record data statistics.It is original
Current data carries out leak subtraction correction by software, and TRPA1 current amplitude is measured in+100mV.Every block of PPC plate of experiment will all have
The dosage effect data of one HC030031 are as positive control, such as the IC of HC03003150Value is more than to obtain on previous every block of plate
IC50At 3 times of average value, repetition measurement will be carried out.Compound dose-effect curve and IC50By GraphPad Prism 5.02
(GraphPad Software, San Diego, CA) is fitted calculating.
Embodiment 1
The compound of the present invention (1-2) inhibits the active IC of transient receptor potential channel protein TRPA150Measurement experiment result
Two kinds of marketed drugs of the invention are automated with the survey of patch-clamp detection by IonWorks Barracuda (IWB)
Method for testing carries out IC50Inhibitory activity test, activity data is as shown in table 1, and two kinds of marketed drugs are relatively strong to inhibiting TRPA1 to have
Activity, half effective inhibition concentration IC50For 11.67 μM and 32.56 μM.
Inhibitory activity data (IC of 1. compound of table (1-2) to TRPA150,μM)
Embodiment 2
Medicine box
A kind of following medicine box is prepared, the medicine box includes:
(1) the first container, and the first pharmaceutical preparation (such as tablet) in the container, said preparation contain following work
Property ingredient；
(2) second container, and the second pharmaceutical preparation (such as tablet) in the container, said preparation contain following work
Property ingredient；
And (3) operation instructions.
The compound of the present invention 1, compound 2 are two kinds of typical marketed drugs, in vitro can potent inhibition instantaneously by
The activity of bulk potential channel protein TRPA1, thus be expected to exploitation at novel therapeutic pain, inflammation, respiratory disorder (asthma, cough,
Chronic Obstructive tuberculosis), itch related with oxidative stress, reduce urinary-tract disorders, inflammatory bowel disease drug.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (7)
1. the purposes of a kind of 1 compound represented of formula or its pharmaceutically acceptable salt, which is characterized in that be used to prepare medicine group
Object is closed, described pharmaceutical composition is for inhibiting transient receptor potential channel protein TRPA1；
2. purposes as described in claim 1, which is characterized in that the pharmaceutically acceptable salt of 1 compound of formula are as follows:
3. purposes as claimed in claim 1 or 2, which is characterized in that described pharmaceutical composition is by inhibiting transient receptor potential
Channel protein TRPA1 treats disease selected from the group below: pain, inflammation, respiratory disorder, itch, urinary-tract disorders, inflammatory bowel
Disease.
4. purposes as described in claim 1, which is characterized in that contain the formula of 0.001-99wt% in the pharmaceutical composition
1 compound or its pharmaceutically acceptable salt, are based on the total weight of the composition.
5. purposes as described in claim 1, which is characterized in that the formula 1 in the pharmaceutical composition containing 0.1-90wt%
Compound or its pharmaceutically acceptable salt, are based on the total weight of the composition.
6. purposes as described in claim 1, which is characterized in that the formula 1 in the pharmaceutical composition containing 1-80wt% is changed
Object or its pharmaceutically acceptable salt are closed, is based on the total weight of the composition.
7. a kind of active method of inhibition transient receptor potential channel protein TRPA1 that external non-therapeutic is nondiagnostic, special
Sign is, transient receptor potential channel protein is contacted with 1 compound of formula or its pharmaceutically acceptable salt, to inhibit
The activity of transient receptor potential channel protein, wherein 1 compound of formula is as described in the appended claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610617423.7A CN106220562B (en) | 2016-07-29 | 2016-07-29 | The new application of two kinds of quinoline ring class drugs |
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| EP1024833A1 (en) * | 1996-07-11 | 2000-08-09 | Farmarc Nederland B.V. | Pharmaceutical composition containing acid addition salt of basic drug |
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