CN106214670A - The new application of amide-type medicine - Google Patents
The new application of amide-type medicine Download PDFInfo
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- CN106214670A CN106214670A CN201610589481.3A CN201610589481A CN106214670A CN 106214670 A CN106214670 A CN 106214670A CN 201610589481 A CN201610589481 A CN 201610589481A CN 106214670 A CN106214670 A CN 106214670A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
Abstract
The invention provides the new application of amide-type 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 amide-type medicine and lead at suppression transient receptor potential
The application of road albumen (TRPA1) aspect.
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, found when studying fruit bat visual transduction system by Minke etc. first.
Follow-up study is found that again a series of TRP family passage member.According to about 30 kinds of TRP passages found in mammal
Sequence homology, is divided into altogether 6 subfamilies, i.e. TRPC, TRPV, TRPM, TRPML, TRPA and TRPP.The C end of TRP passage
It is respectively positioned in cell membrane with N end, and 6 membrane spaning domains containing S1-S6.Wherein part combination on domain S1-S4
Reaction site is probably gate aperture, but lacks positive charge amino acid residue as voltage-gated channel at S4 domain, mostly
The TRP of number has the most weak voltage sensitivity, lacks selection (PCa/PNa ratio is less than 10).S5-S6 membrane spaning domain parent
Formation duct, pool, and intracytoplasmic S6 end monocycle constitute a low gate, it can by switch regulation and control sun from
Son enters passage.
Letter " A " in TRPA1 refers to ankyrin (Ankyrin), and it is distinguished out in TRP family and is because
At least there are 14 ankyrin repeats in the N end of TRPA1, higher than 3-4 repetitive sequence of other subfamilies.2 spirals
Calcium binding motif domain is present in the N end of TRPA1, but the effect of domain is unclear.Except the critical function of N end, people
Find that the sudden change of C end single amino acids of TRPA1 can be greatly reduced the electric current of TRPA1.Current research shows, one is positioned at
The acquired function mutation of the S4 transmembrane structure of TRPA1 can cause the pain syndrome of familial onset, and this discovery provides
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 to report, Herba Menthae, as the agonist of TRPM8, has double-hump effect: at height to TRPA1
Suppress TRPA1 during concentration, during low concentration, activate TRPA1.In addition to exogenous agonistic agent, current research shows, in tissue injury, inflammation
The endogenous compound 4-hydroxyl nonenoic acid discharged during disease, oxidative stress and 15-deoxidation-12,14 prostaglandin J2 are permissible
Activate TRPA1.Current research finds, in the activation process of TRPA1, agonist is by the N end cysteine residues with TPRA1
Covalent interaction activates TRPA1.In addition to both the above biochemistry activated pathway, TRPA1 passage also can be by nocuity low temperature
Activate with mechanical stimulus.
Research in recent years finds, TRPA1 passage is relevant to the disease such as pain, neuropathy.At present, studies in China is less, but
External drugmaker has been developed for a series of hybar X class TRPA1 inhibitor, and TRPA1 passage also becomes new type analgesic
Study hotspot.Multiple technologies means, specify that in pain by middle TRPA1's including RNA interference, gene knockout etc. at present
Effect.The acute pain of TRPA1 antagonist and 1 phase of chronic pain and 2 clinical trial phases are just in the planning stage, to replace tradition
The Endorphins analgesic used.TRPA1, as the novel targets of analgesic, will open up the research direction of new type analgesic.
People are also in the function and effect understanding TRPA1 passage that deepen continuously, and it is anti-that current research finds that its blocker has
Depression and angst resistance effect.Additionally, TRPA1 is it is verified that be treatment inflammation, respiratory disorder (asthma, cough, Chronic Obstructive
Pneumonopathy), pruritus, urinary tract infection and the target of inflammatory bowel.Ge great drugmaker is the most active in this research field.
Summary of the invention
It is an object of the invention to provide a kind of suppression transient receptor potential channel protein (TRPA1) activity compound and
Its 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, they are used for preparing a pharmaceutical composition or preparation,
Described pharmaceutical composition or preparation suppress transient receptor potential channel protein TRPA1 for (a)；(b) treatment and transient receptor electricity
The disease that bit port albumen is relevant；
In formula,
R1For H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, wherein said replacement
Refer to that there is one or more substituent group selected from lower group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkane
Base)2；
R2For H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C3-C8Cycloalkyl or
Wherein said replacement refers to have one or more substituent group selected from lower group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkane
Base) ,-N (C1-C3Alkyl)2,
M is 1,2,3,4 or 5；
Ra and Rb is each independently selected from: H, C1-C3Alkyl or C1-C3Haloalkyl or C3-C6Cycloalkyl；
R3Being divalent linker for-Lp-Z, the most each L, p is the integer of 0-5,
Z is substituted or unsubstituted phenyl, substituted or unsubstituted C5-C7Cycloalkyl, substituted or unsubstituted 5-7 unit are miscellaneous
Ring, described heterocycle contains 1-3 the hetero atom selected from N, O, S；Wherein said replacement refers to have one or more selected from lower group
Substituent group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2。
In another preference, described Z is substituted or unsubstituted phenyl.
In another preference, described Z is substituted or unsubstituted to contain a N heteroatomic 5-7 unit heterocycle.
In another preference, described containing N heteroatomic 5-7 unit heterocycle be connect on N substituted or unsubstituted
C1-C6The heterocycle of alkyl.
In another preference, each L is independently selected from-CH=CH-,-CH2-CH2-,-NH-or a combination thereof.
In another preference, R2For methyl orWherein, m is 1,2,3,4 or 5.
In another preference, R3ForWherein, n is 1,2,3,4 or 5.
In another preference, m is 3.
In another preference, n is 3.
In another preference, R1For H or methyl.
In another preference, R3For
In another preference, R1And R2It is identical.
In another preference, R1And R2It it is all methyl.
In another preference, described A formula compound includes following compound or its pharmaceutically acceptable salt:
In another preference, described A formula compound includes one or more compounds 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 provided that a kind of pharmaceutical composition, it contain (a) formula 1 compound or its pharmaceutically
Acceptable salt, and optical isomer or its pharmaceutically acceptable salt；(b) formula 2 compound or it is pharmaceutically acceptable
Salt, and optical isomer or its pharmaceutically acceptable salt；And (c) pharmaceutically acceptable carrier
In another preference, the weight ratio of described component (a) and component (b) is 1:20 to 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) and (b) is 0.001-99wt%,
Preferably 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, 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, 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 the activity of transient receptor potential channel protein,
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 suppressing transient receptor potential channel protein TRPA1, including
Step: using formula A compound to the object needed, wherein said formula A compound is as described in first aspect present invention.
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 show compound 1 and suppresses the amount effect relation curve figure of TRPA1 activity.
Detailed description of the invention
The present inventor, through extensively and in depth studying, have unexpectedly discovered that class formation amide-type as shown in formula A first
Compound can suppress the activity of TRPA1 significantly.Experiment shows, described formula A compound TRPA1 is had preferably suppress effect
Really.The formula A compound of the present invention can be used for the treatment pain relevant to TRPA1 target spot, inflammation, respiratory disorder, pruritus, urinary tract barrier
Hinder, inflammatory bowel etc..On this basis, the present invention is completed.
Term
Term " C1-C8 alkyl " refers 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 " C1-C3 alkyl " refers to the straight or branched alkyl with 1-3 carbon atom, such as methyl, ethyl, propyl group or
Similar group.
Term " C1-C3Haloalkyl " refer to the straight or branched alkyl with the halogen substiuted of 1-3 carbon atom, such as halogen
Acute pyogenic infection of nails base, halogenated ethyl, halopropyl, haloisopropyl or similar group.
Term " C3-C8 cycloalkyl " refers to the cycloalkyl with 3-8 carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta,
Suberyl or similar group.
Term " C3-C6 cycloalkyl " refers to the cycloalkyl with 3-6 carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta,
Or similar group.
Term " C5-C7 cycloalkyl " refers to the cycloalkyl with 5-7 carbon atom, such as cyclopenta, cyclohexyl or similar base
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.
Active component
As used herein, " the compounds of this invention " or " formula A compound " is used interchangeably, refer to the compound shown in formula A,
Or its raceme, corresponding isomer or its pharmaceutically acceptable salt.Should be understood that this term also includes the mixing of said components
Thing.
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.
Cinanserin, is the medicine of a kind of SARS-COV, can with schizophrenia, but this compound is not as people
Listed with medicine.Bupivacaine hydrochloride is amide-type long-lasting local anesthesia medicine, it is adaptable to local infiltration anesthesia, peripheral nervous resistance
Stagnant and block inside vertebral canal.Its anesthesia duration is longer 2-3 times than lidocaine hydrochloride, and the spread is similar with lidocaine hydrochloride.To following
The impact of ring and breathing is less, to tissue nonirritant, do not produce metahemoglobin, usual amounts to cardiovascular function without shadow
Ring, when consumption is big can hyperamization drops, decreased heart rate.Beta-receptor is had obvious blocking effect.Levobupivacaine hydrochloride is acyl
Amine local anesthetic, is mainly used in surgery Epidural Block.Bupivacaine is a kind of local anesthetics of amide derivatives, body accumulation
Few, acting duration length (can maintain 5 hours), is a kind of safer long effective local anesthetic.It is mainly used in epidural block fiber crops
Liquor-saturated.
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, respiratory disorder, pruritus, urinary tract infection and inflammatory bowel
Target.
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, inflammation, respiratory disorder, pruritus, urinary-tract disorders, inflammatory bowel.It is preferred that described respiratory disorder is selected from lower group: roar
Breathe heavily, 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) activity.Described
Compositions include (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.
Additionally, the transient receptor potential channel protein of the present invention (TRPA1) inhibitor also can make together with other therapeutic agents
With.
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..
Main advantages of the present invention include:
A the formula A compound of () present invention has significant 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 the formula A compound of () present invention has good exploitation for the treatment of the multiple disease relevant to TRPA1 target spot
Application prospect.
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 percentage by weight and parts by weight.
Material
Compound 1,2,3 and 4 is commercially available following compound:
Universal method
IonWorks Barracuda (IWB) automatization patch-clamp detection: by the HEK293 cell of stable expression mTRPA1,
Containing the DMEM culture medium of 15g/mL Blasticidin S HCl, 200g/mL Hygromycin B and 10%FBS serum, put
In the culture bottle of T175, put into 37 DEG C, 5%CO2Incubator in cultivate, grow into～when 80% until cell density, remove
Culture fluid, rinses one time with the phosphate buffer (PBS) without calcium and magnesium, and the Trypsin adding 3mL digests 2 minutes, adds 7mL training
Nutrient solution terminates digestion.Cell is collected the centrifugation 3 minutes with 800 rev/min in the centrifuge tube of 15mL, removes supernatant
After liquid, the extracellular fluid that cell adds proper volume is resuspended, makes cell density control 2～3 × 106/ mL, and for IWB
Experiment.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).Both sexes are mould
Element B becomes 28mg/mL with experimental day DMSO Fresh, then is configured to the final concentration of 0.1mg/mL with intracellular fluid.
IWB tests population in use patch clamp (population patch clamp, PPC) plate, and all detection process is by instrument
Device is automatically performed.In 384 holes of PPC plate, add extracellular fluid, and under PPC plate, (i.e. in plenum), add intracellular fluid
After, the Cell sap adding 6L carries out sealing-in test, and finally changed into by the intracellular fluid in plenum containing amphotericin B is intracellular
Liquid, forms whole-cell recording technique pattern after making the cell perforation of sealing-in.The sample frequency of record TPRA1 electric current is 10kHz, cell clamp
Making at 0mV, voltage stimulates order (channel protocol) to be the 300ms slope (ramp) from-100mV to+100mV
Voltage, every 10s applies voltage to be stimulated, and 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
By approach described above, compound 1,2,3 and 4 is carried out IC50Inhibitory activity is tested.
Result is as shown in table 1 below: compound 1,2,3 and 4 of the present invention is transient receptor potential channel protein
(TRPA1) activity inhibitor, the activity of described 1,2,3 and 4 couples of TRPA1 of compound has significant inhibitory action.
Table 1
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；
(2) second container, and it is positioned at first pharmaceutical preparation (such as tablet) of described container, said preparation contains following work
Property composition；
And (3) operation instructions.
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 use for preparation one pharmaceutical composition or preparation, described pharmaceutical composition or preparation
Transient receptor potential channel protein TRPA1 is suppressed in (a)；B disease that () treatment is relevant to transient receptor potential channel protein；
In formula,
R1For H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, wherein said replacement refers to tool
There is one or more substituent group selected from lower group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
R2For H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C3-C8Cycloalkyl or
Wherein said replacement refers to have one or more substituent group selected from lower group: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkane
Base) ,-N (C1-C3Alkyl)2,
M is 1,2,3,4 or 5；
Ra and Rb is each independently selected from: H, C1-C3Alkyl or C1-C3Haloalkyl or C3-C6Cycloalkyl；
R3Being divalent linker for-Lp-Z, the most each L, p is the integer of 0-5,
Z is substituted or unsubstituted phenyl, substituted or unsubstituted C5-C7Cycloalkyl, substituted or unsubstituted 5-7 unit heterocycle, institute
State heterocycle and contain 1-3 the hetero atom selected from N, O, S；Wherein said replacement refers to have one or more replacement selected from lower group
Base: halogen ,-OH ,-NH2、-CN、-NH(C1-C3Alkyl) ,-N (C1-C3Alkyl)2。
2. purposes as claimed in claim 1, it is characterised in that R3For
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 A formula compound includes the one or many selected from lower group
Kind compound:
5. purposes as claimed in claim 1, it is characterised in that described transient receptor potential channel protein TRPA1 is people's wink
Time receptor potential channel protein TRPA1.
6. purposes as claimed in claim 1, 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.
7. 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.
8. 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
9. 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.
10. the method for the suppression transient receptor potential channel protein TRPA1 activity of an external non-therapeutic, 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 contacts, thus suppresses the activity of transient receptor potential channel protein, wherein said formula Aization
Compound is as described in the appended claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610589481.3A CN106214670B (en) | 2016-07-25 | 2016-07-25 | Application of amide medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610589481.3A CN106214670B (en) | 2016-07-25 | 2016-07-25 | Application of amide medicine |
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| CN1133010A (en) * | 1993-10-13 | 1996-10-09 | 奇罗斯恩有限公司 | Analgesic agent and its use |
| CN1249685A (en) * | 1997-03-03 | 2000-04-05 | 达尔文发现有限公司 | Use of levobupivacaine or ropivacaine in treating migraine |
| EP1787679A1 (en) * | 2005-07-29 | 2007-05-23 | Laboratorios Del Dr. Esteve, S.A. | Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain |
| CN1989099A (en) * | 2004-06-07 | 2007-06-27 | 奥斯瓦道·克鲁兹基金会 | Compounds derived from lidocaine, pharmaceutical compositions, use and method of treatment, prevention or inhibition of diseases |
| CN101959861A (en) * | 2008-01-04 | 2011-01-26 | 雅培制药有限公司 | Trpa1 antagonists |
| CN102725401A (en) * | 2009-07-10 | 2012-10-10 | 哈佛大学校长及研究员协会 | Permanently charged sodium and calcium channel blockers as anti-inflammatory agents |
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| CN1133010A (en) * | 1993-10-13 | 1996-10-09 | 奇罗斯恩有限公司 | Analgesic agent and its use |
| CN1249685A (en) * | 1997-03-03 | 2000-04-05 | 达尔文发现有限公司 | Use of levobupivacaine or ropivacaine in treating migraine |
| CN1989099A (en) * | 2004-06-07 | 2007-06-27 | 奥斯瓦道·克鲁兹基金会 | Compounds derived from lidocaine, pharmaceutical compositions, use and method of treatment, prevention or inhibition of diseases |
| EP1787679A1 (en) * | 2005-07-29 | 2007-05-23 | Laboratorios Del Dr. Esteve, S.A. | Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain |
| CN101959861A (en) * | 2008-01-04 | 2011-01-26 | 雅培制药有限公司 | Trpa1 antagonists |
| CN102725401A (en) * | 2009-07-10 | 2012-10-10 | 哈佛大学校长及研究员协会 | Permanently charged sodium and calcium channel blockers as anti-inflammatory agents |
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