CN106220562A - The new application of two kinds of quinoline ring class medicines - Google Patents
The new application of two kinds of quinoline ring class medicines Download PDFInfo
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- CN106220562A CN106220562A CN201610617423.7A CN201610617423A CN106220562A CN 106220562 A CN106220562 A CN 106220562A CN 201610617423 A CN201610617423 A CN 201610617423A CN 106220562 A CN106220562 A CN 106220562A
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- PUFQVTATUTYEAL-UHFFFAOYSA-N CCCCOc1nc2ccccc2c(C(NCCN(CC)CC)=O)c1 Chemical compound CCCCOc1nc2ccccc2c(C(NCCN(CC)CC)=O)c1 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
-
- 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
Abstract
The invention provides the new application of quinoline ring class medicine.Specifically, the invention provides the compound shown in formula A or its optical isomer or its racemic modification or its solvate or the purposes of its pharmaceutically acceptable salt, they are used for preparing a pharmaceutical composition or preparation, described pharmaceutical composition or preparation and suppress transient receptor potential channel protein TRPA1 for (a)；B disease that () treatment is relevant to transient receptor potential channel protein, in formula, each group definition is as noted in the discussion.
Description
Technical field
The present invention relates to medicinal chemistry art, relate more specifically to quinoline ring class medicine and it is at suppression transient receptor potential
Application in terms of channel protein TRPA1.
Background technology
Transient receptor potential channel (Transient receptor potential, TRP) is that a class is present in cell membrane
On the superfamily protein that constitutes of important cationic channel, first by Minke etc. studying fruit bat visual transduction system when
Find.Research subsequently is found that again a series of TRP family passage member.Lead to according to about 30 kinds of TRP found in mammals
The sequence homology in road, is divided into altogether 6 subfamilies, i.e. TRPC, TRPV, TRPM, TRPML, TRPA and TRPP.TRP passage
C end and N end be respectively positioned in cell membrane, and containing 6 membrane spaning domains of S1-S6.Wherein part knot on domain S1-S4
The reaction site closed may be by gating aperture, but lacks positive charge amino acid residue as valtage-gated logical at S4 domain
Road, most TRP has the most weak voltage sensitivity, lacks selection (PCa/PNa ratio is less than 10).S5-S6 cross-film
Formation duct, domain hydrophilic area, and constitute a low gate at intracytoplasmic S6 end monocycle, it can be by opening
Close regulation and control cation and enter passage.
Letter " A " in TRPA1 refers to ankyrin (Ankyrin), it be distinguished out in TRP family be by
The ankyrin repeat at least existed in the N end of TRPA1 is 14, higher than 3～4 repetitions of other subfamilies.2 spirals
Calcium binding motif domain be present in the N end of TRPA1, but the effect of domain is unclear.Except the critical function of N end,
It is found that the sudden change of the C end single amino acids of TRPA1 can be greatly reduced the electric current of TRPA1.Up-to-date research shows, a position
Acquired function mutation in the S4 transmembrane structure of TRPA1 can cause the pain syndrome of familial onset, and this finds to provide
The TRP ion channel disease that first case pain is relevant.
Activating TRPA1 passage has number of ways, TPR passage generally individually can be activated by phospholipase C, and g protein coupled receptor exists
The activation of TRPA1 there occurs effect；In ligand activation approach, a series of chemical stimulation all can activate TRPA1, is reported
The agonist in road includes: cinnamic aldehyde (Cortex Cinnamomi), garlicin and diallyl disulfide (Bulbus Allii), isothiocyanic acid salt (mustard oil, wasabi,
Wasabia japonic (Euterma Wasabi)), acrylic aldehyde (medicated cigarette), 9-tetrahydrocannabinol (Fructus Cannabis), diallyl disulfide, mustard oil (mustard), icilin, water
Poplar acid methyl ester (wintergreen oil) etc..Having document recently to report, Herba Menthae, as the agonist of TRPM8, has a double-hump effect to TRPA1:
Suppress TRPA1 when high concentration, during low concentration, activate 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 injury, inflammation, oxidative stress and 15-deoxidation-12,
14 prostaglandin J2 activate.Up-to-date research finds, in the activation process of TRPA1, agonist is by N end half Guang with TPRA1
Histidine residue covalent interaction activates TRPA1.In addition to both the above biochemistry activated pathway, TRPA1 passage also can be hindered
Evil property low temperature and mechanical stimulus activate.
Summary of the invention
It is an object of the invention to provide a kind of suppress transient receptor potential channel protein TRPA1 activity compound and
Application.
In a first aspect of the present invention, it is provided that the compound shown in a kind of formula A, or its optical isomer or its raceme
Body or its solvate or the purposes of its pharmaceutically acceptable salt, it is characterised in that be used for preparing pharmaceutical composition or system
Agent, described pharmaceutical composition or preparation suppress transient receptor potential channel protein TRPA1 for (a)；(b) treatment and transient receptor
The disease that current potential channel protein is relevant；
In formula,
X1 indicate without, or 1 or 2 selected from the substituent group of lower group: halogen ,-OH, substituted or unsubstituted C1-C8Alkyl, take
Generation or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C1-C8Alkoxyl or substituted or unsubstituted C3-C8Cycloalkanes oxygen
Base, wherein said replacement refers to have one or more substituent group selected from lower group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3
Alkyl) ,-N (C1-C3Alkyl)2；
X2 indicate without, or 1,2 or 3 selected from the substituent groups of lower group: substituted or unsubstituted C1-C8Alkoxyl, replacement or
Unsubstituted C3-C8Cycloalkyloxy or halogen, wherein said replacement refers to have one or more substituent group selected from lower group: halogen
Element ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
R1 is-L-Z group,
Wherein L is selected from lower group :-C (O)-NRc-Ym-(C1-C4Alkylidene)-,-NRc-Ym-(C1-C4Alkylidene)-, wherein Y
For substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C4-C10Heteroaryl, described heteroaryl contain 1-3 selected from N,
The hetero atom of O, S；M is 0 or 1, and wherein said replacement refers to have one or more substituent group selected from lower group: halogen ,-OH,
C1-C3Alkyl, C1-C3Haloalkyl ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
Rc is selected from: H, C1-C6Alkyl or C1-C6Haloalkyl or C3-C6Cycloalkyl；
Z isRa and Rb is each independently selected from: H, C1-C6Alkyl or C1-C6Haloalkyl or C3-C6Cycloalkanes
Base.
In another preference, Ra and Rb is each independently selected from: C1-C6Alkyl or C1-C6Haloalkyl.
In another preference, described formula A compound has a structural formula A1:
In formula,
R1 is as defined above；
R2 is substituted or unsubstituted C1-C8Alkoxyl or substituted or unsubstituted C3-C8Cycloalkyloxy；Wherein, described
Replacement refer to have one or more substituent group selected from lower group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-
C3Alkyl)2；
R3 is H, substituted or unsubstituted C1-C8Alkoxyl or halogen, wherein said replacement refers to have one or more
Substituent group selected from lower group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2。
In another preference, Ra and Rb is each independently selected from: C1-C6Alkyl or C1-C6Haloalkyl.
In another preference, m=0.
In another preference, m=1, and the substituted or unsubstituted phenyl of Y=.
In another preference, Ra=Rb=C2Alkyl.
In another preference, Rc=H.
In another preference, R2=-O-(C4Alkyl).
In another preference, R3=H or Cl.
In another preference, described R1 is selected from:
In another preference, described A formula compound includes following compound or its pharmaceutically acceptable salt:
In another preference, described formula A compound is selected from lower group:
In another preference, described transient receptor potential channel protein TRPA1 is people's transient receptor potential channel egg
White TRPA1.
In another preference, the described disease relevant to transient receptor potential channel protein is selected from lower group: pain, inflammation
Disease, respiratory disorder, pruritus, urinary-tract disorders, inflammatory bowel.
In another preference, described respiratory disorder is selected from lower group: asthma, cough, Chronic Obstructive pneumonopathy.
In another preference, containing 0.001-99wt% in pharmaceutical composition described in described pharmaceutical composition, preferably
The ground formula A compound of 0.1-90wt%, more preferably 1-80wt% or its optical isomer or its racemic modification or its solvation
Thing or its pharmaceutically acceptable salt, be based on the total weight of the composition.
In another preference, described pharmaceutical composition or preparation also can be containing other drug active component or pharmaceutically
Acceptable carrier.
In a second aspect of the present invention, it is characterised in that containing (a) formula 1 compound or its pharmaceutically acceptable salt, and
Its optical isomer or its pharmaceutically acceptable salt；(b) formula 2 compound or its pharmaceutically acceptable salt, and optics is different
Structure body or its pharmaceutically acceptable salt；And (c) pharmaceutically acceptable carrier,
In another preference, when described active component contains two kinds of components, the weight ratio 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 preference, in described pharmaceutical composition, the total amount of component (a) is 0.001-99wt%, preferably
Ground 0.1-90wt%, more preferably 1-80wt%, be based on the total weight of the composition.
In another preference, described pharmaceutical composition or preparation also can be containing other drug active component or pharmaceutically
Acceptable carrier.
In a third aspect of the present invention, it is provided that a kind of medicine box, it is characterised in that described medicine box includes:
(1) first container, and it is positioned at the first pharmaceutical composition of described container, the first described pharmaceutical composition contains
There are formula 1 compound or its pharmaceutically acceptable salt, and optical isomer or its pharmaceutically acceptable salt, and pharmaceutically
Acceptable carrier；
(2) second container, and it is positioned at the second pharmaceutical composition of described container, the second described pharmaceutical composition contains
There are formula 2 compound or its pharmaceutically acceptable salt, and optical isomer or its pharmaceutically acceptable salt；And pharmaceutically
Acceptable carrier；
And the operation instructions that (3) are optional.
In a fourth aspect of the present invention, it is provided that the suppression transient receptor potential channel protein of a kind of external non-therapeutic
The method of TRPA1 activity, it is characterised 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 contact, thus suppress transient receptor potential channel
The activity of albumen, wherein said formula A compound is as described in first aspect present invention.
In a fifth aspect of the present invention, it is provided that a kind of method of suppression transient receptor potential channel protein TRPA1,
It is characterized in that, including step: use formula A compound, the wherein said formula A compound such as present invention first to the object needed
Described in aspect.
In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment)
Can be combined with each other between each technical characteristic that body describes, thus constitute new or preferred technical scheme.As space is limited, exist
This tires out the most one by one states.
Accompanying drawing explanation
Fig. 1 is the amount effect relation curve figure of amodiaquine hydrochlorate (1) suppression TRPA1 activity.
Detailed description of the invention
The present inventor, through extensively and in depth studying, have unexpectedly discovered that class formation compound as shown in formula A first
The activity of TRPA1 can be suppressed significantly.Experiment shows, described formula A compound has preferable inhibition to TRPA1, this
It is relevant with oxidative stress that the formula A compound of invention can be used for pain, inflammation, respiratory disorder that treatment is correlated with TRPA1 target spot
Pruritus, urinary-tract disorders, inflammatory bowel etc..On this basis, the present invention is completed.
Term
Term " C1～C8Alkoxyl " refer to the straight or branched alkyl 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 " refer to the straight or branched alkyl with 1～8 carbon atom, such as methyl, ethyl, propyl group,
Isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.
Term " C3～C8Cycloalkyl " refer to the cycloalkyl with 3～8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopenta,
Suberyl or similar group.
Term " C2～C6Thiazolinyl " refer to the thiazolinyl with 1～6 carbon atom, such as vinyl, acrylic, isopropenyl, fourth
Thiazolinyl, isobutenyl, secondary cyclobutenyl, tertiary cyclobutenyl or similar group.
Term " 5-7 unit heterocycle " refers to have one or more, and preferably 1-3 heteroatomic circulus, described ring can
To be saturated or undersaturated ring.
Term " halogen " refers to F, Cl, Br and I.
Term " C6-C10Aryl " refer to the cyclic group with aromatic structure, such as phenyl, naphthyl.
Term " C4-C10Heteroaryl " refer to the cyclic group that in aryl, one or more carbon atoms are formed after being exchanged for heteroatoms
Group, wherein hetero atom is selected from N, O or S.The example of heteroaryl includes (but being not limited to): pyridine radicals, pyridazinyl, pyrimidine radicals, pyrrole
Piperazine base.
Active component
As used herein, " the compounds of this invention ", " the quinoline ring class medicine of the present invention and derivant thereof " or " formula A chemical combination
Thing " it is used interchangeably, refer to the compound shown in formula A or its raceme, corresponding isomer or its pharmaceutically acceptable salt.Should
Understanding, this term also includes the mixture of said components.
The compounds of this invention is not only inhibited to TRPA1, and other member in TRP family is also had certain suppression
Effect.
In formula, each group is as defined above.
In the present invention, the pharmaceutically acceptable salt of formula A compound is also included.Term " pharmaceutically acceptable salt " refers to
The salt being suitable as medicine that the compounds of this invention is formed with acid or alkali.Pharmaceutically acceptable salt includes inorganic salt and organic
Salt.The one preferred salt of class is the salt that the compounds of this invention is formed with acid.The acid suitably forming salt includes, but are not limited to: hydrochloric acid,
The mineral acids such as hydrobromic acid, Fluohydric acid., sulphuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propanoic 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 acid such as benzenesulfonic acid；With
And the acidic amino acid such as aspartic acid, glutamic acid.
The formula A compound of the present invention can use method well known to those skilled in the art in prior art to be prepared, right
The response parameter of each step is not particularly limited.Additionally, the typical compound of the present invention also can be obtained by commercially available mode.
As used herein, in formula A compound, if there is chiral carbon atom, then chiral carbon atom can be R configuration,
Can also be S configuration, or the mixture of the two.
Camoquin is aminoquinolines antimalarial, and Antimalarial is similar to chloroquine, acts on erythrocyte stage malaria
Protozoon, can control rapidly clinical symptoms.In addition, the plasmodium also resisting chloroquine is the most effective.Untoward reaction is less, has head
Swoon, vomit and diarrhoea etc..Can be used for the bad person of anemia of pregnant woman, child and liver function.
Hydrochloric acid stage caine is anesthesia quasi drugs, and in the local anaesthetics of clinical practice, stage caine is to act on the strongest, toxicity
Maximum, the longest one of holding time.The anesthetic potency of drug administration by injection is 15 times of procaine, the biggest 15 times of toxicity.Onset
Relatively slow, about 15min, but the continuous action time is procaine 3 times.Local irritation is little, 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 a class is present in
The superfamily protein that important cationic channel on cell membrane is constituted.Research finds, TRPA1 passage and pain, neuropathy etc.
Disease is correlated with.Additionally, it is verified that, TRPA1 still treats inflammation, the respiratory disorder pruritus relevant with oxidative stress, urinary tract
Infect and the target of inflammatory bowel.
Generally, TRPA1 gene can use conventional method (such as PCR or complete synthesis) to obtain, and is then connected into the expression vector of routine
(such as pcDNA5, pcDNA3) etc..Then, described expression vector is proceeded to suitable host cell (as yeast cells, Chinese hamster ovary celI,
293 cells, escherichia coli etc.), thus obtain the cell strain expressing TRPA1.The cell strain of described expression TRPA1 can directly be used
In test, it is possible to be used for testing by isolated TRPA1.
In the present invention, TRPA1 includes that people and non-human mammal (such as rodent such as mice and rat) are originated
TRPA1。
Purposes
Present invention also offers a kind of method suppressing transient receptor potential channel protein TRPA1, and treatment is with instantaneous
The method of the disease that receptor potential channel protein is relevant.
The above-mentioned formula A compound of the present invention can be used for suppressing TRPA1, and then prevent or treat and transient receptor potential channel
The disease that albumen is relevant.
In the present invention, the example of relevant to transient receptor potential channel protein disease includes (but being not limited to): pain
Bitterly, inflammation, respiratory disorder, pruritus, urinary-tract disorders, inflammatory bowel.It is preferred that described respiratory disorder is selected from lower group: asthma,
Cough, Chronic Obstructive pneumonopathy.
In one embodiment, the invention provides the suppression transient receptor potential channel protein of a kind of external non-therapeutic
The method of TRPA1 activity, including: the most in vitro in cultivating system, by transient receptor potential channel protein or express described egg
White cell and formula A compound (or its optical isomer or its racemic modification or its solvate or it is pharmaceutically acceptable
Salt) contact, thus suppress the activity of transient receptor potential channel protein.
Present invention also offers a kind of method suppressing transient receptor potential channel protein TRPA1, the method can be to control
The property treated or non-therapeutic.Generally, the method comprising the steps of: uses the formula A compound of the present invention to the object needed.
Preferably, described object includes people and non-human mammal (rodent, rabbit, monkey, domestic animal, Canis familiaris L., cat etc.).
Compositions and application process
The invention provides a kind of compositions for suppressing transient receptor potential channel protein TRPA1.Described combination
Thing includes (but being not limited to): pharmaceutical composition, food compositions, dietary supplement, beverage composition for treating dental erosion etc..
In the present invention, described pharmaceutical composition can be directly used for disease treatment, such as, and controlling for respiratory disorder
Treat.
Present invention also offers 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): saline, buffer, glucose, water, glycerol, second
Alcohol, powder, and combinations thereof.Pharmaceutical preparation should match with administering mode.
As a example by pharmaceutical composition, the compositions of the present invention can be to be made into injection form, such as with normal saline or contain
The aqueous solution having glucose and other adjuvant is prepared by conventional method.The drug regimen of such as tablet and capsule etc
Thing, can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule the most aseptically manufacture.
The drug regimen of the present invention can also be made into powder for Neulized inhalation.
The dosage of active component is therapeutically effective amount, such as about 1 microgram every day/kg body weight-about 5 mg/kg body
Weight.Additionally, the transient receptor potential channel protein TRPA1 inhibitor of the present invention also can be used together with other therapeutic agents.
For the pharmaceutical composition of the present invention, required object can be applied to (such as people and the inhuman food in one's mouth by the way of conventional
Breast animal).Representational method of application includes (but being not limited to): oral, injection, Neulized inhalation etc..
When making pharmaceutical composition, it is in mammal by the medicament administration of safe and effective amount, wherein this safe and effective amount
Typically at least about 10 micrograms/kg body weight, and in most of the cases no more than about 8 mg/kg body weight, preferably this agent
Amount is about 10 micrograms/kg body weight-about 1 mg/kg body weight.Certainly, concrete dosage is it is also contemplated that route of administration, 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 the formula A compound of () present invention has preferable inhibition to TRPA1.
B the typical form A compound of () present invention has excellent safety, toxic and side effects is the least or almost non-toxic secondary makees
With.
C pain that the formula A compound of () present invention mediates for TRPA1, inflammation have preferably treats potential.
D the formula A compound of () present invention has been used for the treatment of human diseases by supervision department's approval, so this new application
Discovery can rapidly enter the clinical II phase and test, be conducive to shortening research and development time and reduction R & D Cost.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally 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 condition proposed by manufacturer.Unless otherwise indicated, no
Then percentage ratio and number are calculated by weight.
Material
Compound 1,2 is commercially available following compound:
Compound 1
Compound 2
Universal method
The compound (1-2) of the present invention test experiments to the inhibitory activity of transient receptor potential channel protein TRPA1
Method of testing by the patch-clamp detection of IonWorks Barracuda (IWB) automatization: stably express mTRPA1
HEK293 cell, with containing 15g/mL Blasticidin S HCl, 200g/mL Hygromycin B and 10%FBS serum
DMEM culture medium, be placed in the culture bottle of T175, put into 37 DEG C, 5%CO2Incubator in cultivate, treat that cell density grows
To～when 80%, remove culture fluid, rinse one time with the phosphate buffer (PBS) without calcium and magnesium, the Trypsin adding 3mL digests 2
Minute, add 7mL culture fluid and terminate digestion.Cell is collected in the centrifuge tube of 15mL and is centrifuged 3 minutes with 800 rev/min,
The extracellular fluid that cell adds after removing supernatant proper volume is resuspended, makes cell density control in 2-3 × 106/ mL also uses
Test 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 becomes 28mg/mL with experimental day DMSO Fresh, then is configured to the final concentration of 0.1mg/mL with intracellular fluid.
IWB experiment uses population patch clamp (PPC) plate, and whole detection processes are automatically performed by instrument,
In 384 holes of PPC plate, i.e. add extracellular fluid, and after adding intracellular fluid in i.e. plenum under PPC plate, add 6 μ L's
Cell sap 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 of record TPRA1 electric current is 10kHz, and cell is clamped down at 0mV, electricity
Pressure stimulates order (channel protocol) to be 300ms slope (ramp) voltage from-100mV to+100mV, every 10s
Giving this voltage to stimulate, mTRPA electric current is induced by 300M AITC.
Data record and current amplitude are measured to derive and are completed (version 2.5.3, Molecular by IWB software
Devices Corporation, Union City, CA).The sealing-in impedance hole less than 20M Ω will not record data statistics.Original
Current data is carried out leakage by software and subtracts rectification, and TRPA1 current amplitude records when+100mV.Every block of PPC plate of experiment all will have
The dosage effect data of one HC030031 are as positive control, such as the IC of HC03003150Value exceedes and obtained on every block of plate in the past
IC50During 3 times of meansigma methods, 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 IC of compound (1-2) the suppression transient receptor potential channel protein TRPA1 activity of the present invention50Determination experiment result
The survey that two kinds of marketed drug of the present invention are detected by IonWorks Barracuda (IWB) automatization patch-clamp
Method for testing, carries out IC50Inhibitory activity is tested, and activity data is as shown in table 1, and suppression TRPA1 is had stronger by these two kinds of marketed drug
Activity, half effective inhibition concentration IC50It it is 11.67 μMs and 32.56 μMs.
The table 1. compound (1-2) inhibitory activity data (IC to TRPA150,μM)
Embodiment 2
Medicine box
The following a kind of medicine box of preparation, described medicine box includes:
(1) first container, and it is positioned at first pharmaceutical preparation (such as tablet) of described container, said preparation contains following work
Property composition；
Compound 1
(2) second container, and it is positioned at second pharmaceutical preparation (such as tablet) of described container, said preparation contains following work
Property composition；
Compound 2
And (3) operation instructions.
The compound 1 of the present invention, compound 2 is two kinds of typical marketed drug the most, in vitro can potent suppression is instantaneous is subject to
The activity of bulk potential channel protein TRPA1, be therefore expected to develop into novel therapeutic pain, inflammation, respiratory disorder (asthma, cough,
Chronic Obstructive pneumonopathy) pruritus relevant with oxidative stress, reduce urinary-tract disorders, the medicine of inflammatory bowel.
The all documents mentioned in the present invention are incorporated as reference the most in this application, just as each document by individually
It is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, those skilled in the art can
To make various changes or modifications the present invention, these equivalent form of values fall within the model that the application appended claims is limited equally
Enclose.
Claims (10)
1. the compound shown in formula A, or its optical isomer or its racemic modification or its solvate or its pharmaceutically
The purposes of acceptable salt, it is characterised in that be used for preparing pharmaceutical composition or preparation, described pharmaceutical composition or preparation are used for
(a) suppression transient receptor potential channel protein TRPA1；B disease that () treatment is relevant to transient receptor potential channel protein；
In formula,
X1 indicate without, or 1 or 2 selected from the substituent group of lower group: halogen ,-OH, substituted or unsubstituted C1-C8Alkyl, replacement or
Unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C1-C8Alkoxyl or substituted or unsubstituted C3-C8Cycloalkyloxy, its
Described in replacement refer to have one or more substituent group selected from lower group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkane
Base) ,-N (C1-C3Alkyl)2；
X2 indicate without, or 1,2 or 3 selected from the substituent groups of lower group: substituted or unsubstituted C1-C8Alkoxyl, replacement or do not take
The C in generation3-C8Cycloalkyloxy or halogen, wherein said replacement refers to have one or more substituent group selected from lower group: halogen ,-
OH、-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
R1 is-L-Z group,
Wherein L is selected from lower group :-C (O)-NRc-Ym-(C1-C4Alkylidene)-,-NRc-Ym-(C1-C4Alkylidene)-, wherein Y is for taking
Generation or unsubstituted C6-C10Aryl, substituted or unsubstituted C4-C10Heteroaryl, described heteroaryl contains 1-3 selected from N, O, S
Hetero atom；M is 0 or 1, and wherein said replacement refers to have one or more substituent group selected from lower group: halogen ,-OH, C1-
C3Alkyl, C1-C3Haloalkyl ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
Rc is selected from: H, C1-C6Alkyl or C1-C6Haloalkyl or C3-C6Cycloalkyl；
Z isRa and Rb is each independently selected from: H, C1-C6Alkyl or C1-C6Haloalkyl or C3-C6Cycloalkyl.
2. purposes as claimed in claim 1, it is characterised in that described R1 is selected from:
3. purposes as claimed in claim 1, it is characterised in that described A formula compound includes following compound or its pharmacy
Upper acceptable salt:
4. purposes as claimed in claim 1, it is characterised in that described formula A compound is selected from lower group:
5. purposes as claimed in claim 4, it is characterised in that the described disease relevant to transient receptor potential channel protein
Selected from lower group: pain, inflammation, respiratory disorder, pruritus, urinary-tract disorders, inflammatory bowel.
6. purposes as claimed in claim 1, it is characterised in that contain in pharmaceutical composition described in described pharmaceutical composition
The formula A compound of 0.001-99wt%, preferably 0.1-90wt%, more preferably 1-80wt% or its optical isomer or its outside
Raceme or its solvate or its pharmaceutically acceptable salt, be based on the total weight of the composition.
7. a pharmaceutical composition, it is characterised in that containing (a) formula 1 compound or its pharmaceutically acceptable salt, and optics
Isomer or its pharmaceutically acceptable salt；(b) formula 2 compound or its pharmaceutically acceptable salt, and optical isomer or
Its pharmaceutically acceptable salt；And (c) pharmaceutically acceptable carrier,
8. a medicine box, it is characterised in that described medicine box includes:
(1) first container, and it is positioned at the first pharmaceutical composition of described container, the first described pharmaceutical composition contains formula
1 compound or its pharmaceutically acceptable salt, and optical isomer or its pharmaceutically acceptable salt, and pharmaceutically can connect
The carrier being subject to；
(2) second container, and it is positioned at the second pharmaceutical composition of described container, the second described pharmaceutical composition contains formula
2 compounds or its pharmaceutically acceptable salt, and optical isomer or its pharmaceutically acceptable salt；And pharmaceutically can connect
The carrier being subject to；
And the operation instructions that (3) are optional.
9. the method for the suppression transient receptor potential channel protein TRPA1 activity of an external non-therapeutic, it is characterised in that will
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 contacts, thus suppresses the activity of transient receptor potential channel protein, wherein said formula A chemical combination
Thing is as described in the appended claim 1.
10. the method for a suppression transient receptor potential channel protein TRPA1, it is characterised in that include step: to needs
Object use formula A compound, wherein said formula A compound is as described in the appended claim 1.
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