CN106214670B - Application of amide medicine - Google Patents
Application of amide medicine Download PDFInfo
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- CN106214670B CN106214670B CN201610589481.3A CN201610589481A CN106214670B CN 106214670 B CN106214670 B CN 106214670B CN 201610589481 A CN201610589481 A CN 201610589481A CN 106214670 B CN106214670 B CN 106214670B
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- trpa1
- transient receptor
- receptor potential
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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 a new application of an amide medicine. Specifically, the invention provides an application of a compound shown as a formula A, or an optical isomer or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, which is used for preparing a pharmaceutical composition or a preparation for (a) inhibiting transient receptor potential channel protein TRPA 1; (b) treating diseases related to transient receptor potential channel protein, wherein each group is defined as the specification.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to an amide medicament and application thereof in inhibiting transient receptor potential channel protein (TRPA 1).
Background
Transient Receptor Potential (TRP) channels are a protein superfamily consisting of important cation channels existing on cell membranes, and are discovered by Minke and the like in the research of a visual conduction system of drosophila for the first time. Subsequent studies have in turn found a series of TRP family channel members. Based on the sequence homology of about 30 TRP channels found in mammals, a total of 6 subfamilies are identified, namely TRPC, TRPV, TRPM, TRPML, TRPA and TRPP. Both the C-and N-termini of the TRP channel are located within the cell membrane and contain the 6-transmembrane domain of S1-S6. Where the reaction site for ligand binding on domains S1-S4 might be a gated pinhole, but where the positively charged amino acid residues are absent in the S4 domain as voltage-gated channels, most TRPs have poor voltage sensitivity and lack of selectivity (PCa/PNa ratio less than 10). The hydrophilic region of the S5-S6 transmembrane domain forms a channel, and a single loop at the end of S6 in the cytoplasm forms a low-limit valve which can regulate the cation entering channel by switching.
The letter "a" in TRPA1 refers to Ankyrin (Ankyrin), which is distinguished in the TRP family because at least 14 Ankyrin repeats, higher than 3-4 repeats of other subfamilies, are present at the N-terminus of TRPA 1. The 2-helix calcium binding motif domain is present at the N-terminus of TRPA1, but the role of the domain is not yet clear. In addition to the important function of the N-terminus, mutations in the C-terminal single amino acid of TRPA1 were found to dramatically reduce TRPA1 current. Recent studies have shown that an acquired functional mutation in the S4 transmembrane structure of TRPA1 leads to familial onset pain syndrome, and this finding provides the first instance of a pain-associated TRP ion channel disorder.
There are various ways to activate the TRPA1 channel, the TPR channel can be generally activated by phospholipase C, and G protein coupled receptors play a role in the activation of TRPA 1; in the ligand activation pathway, TRPA1 is activated by a series of chemical stimuli, and reported agonists include cinnamaldehyde (cinnamon), allicin and allicin (garlic), isothiocyanates (mustard oil, wasabi, horseradish), acrolein (cigarette), 9-tetrahydrocannabinol (hemp), diallyl disulfide, mustard oil (mustard), icilin, methyl salicylate (wintergreen oil), and the like. It has been reported in the literature that mint, as an agonist of TRPM8, has a bimodal effect on TRPA 1: TRPA1 was inhibited at high concentrations and TRPA1 was activated at low concentrations. In addition to exogenous agonists, recent studies have shown that the endogenous compounds 4-hydroxynonenoic acid and 15-deoxy-12, 14 prostaglandin J2 released during tissue injury, inflammation, oxidative stress can activate TRPA 1. Recent studies found that during activation of TRPA1, agonists activate TRPA1 by covalently interacting with the N-terminal cysteine residue of TPRA 1. In addition to the above two biochemical activation pathways, the TRPA1 channel may also be activated by noxious hypothermia and mechanical stimuli.
In recent years, the TRPA1 channel is found to be related to diseases such as pain, neuropathy and the like. At present, domestic research is less, but pharmaceutical companies abroad develop a series of pyrimidinedione TRPA1 inhibitors, and the TRPA1 channel also becomes a research hotspot of novel analgesics. The role of TRPA1 in pain perception has been elucidated by various current technical approaches including RNA interference, gene knock-out, etc. Phase 1 and phase 2 clinical trials of TRPA1 antagonists of acute and chronic pain are in the planning phase to replace traditionally used opioid peptide analgesics. TRPA1 as a new target of analgesic drugs will develop the research direction of novel analgesics.
The function and action of the TRPA1 channel are also well understood, and recent studies have found that blockers thereof have antidepressant and anxiolytic effects. In addition, TRPA1 has been demonstrated as a target for the treatment of inflammation, respiratory disorders (asthma, cough, chronic obstructive pulmonary disease), pruritus, urinary tract infections and inflammatory bowel disease. Large pharmaceutical companies are also active in this research area.
Disclosure of Invention
The invention aims to provide a compound for inhibiting transient receptor potential channel protein (TRPA1) activity and application thereof.
In a first aspect of the present invention, there is provided a use of a compound represented by formula a, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition or formulation for (a) inhibiting transient receptor potential channel protein TRPA 1; (b) treating diseases associated with transient receptor potential channel proteins;
in the formula (I), the compound is shown in the specification,
R1is H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, wherein said substitution refers to having one or more substituents selected from the group consisting of: halogen, -OH, -NH2、-CN、 -NH(C1-C3Alkyl), -N (C)1-C3Alkyl radical)2；
R2Is H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, or
Wherein said substitution refers to having one or more substituents selected from the group consisting of: halogen, -OH, -NH2、-CN、-NH(C1-C3Alkyl), -N (C)1-C3Alkyl radical)2，
m is 1, 2, 3, 4, or 5;
ra and Rb are each independently selected from: H. c1-C3Alkyl or C1-C3Haloalkyl, or C3-C6A cycloalkyl group;
R3is-Lp-Z, wherein each L is a divalent linking group, p is an integer from 0 to 5,
z is substituted or unsubstituted phenyl, substituted or unsubstituted C5-C7Cycloalkyl, a substituted or unsubstituted 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, S; wherein said substitution refers to having one or more substituents selected from the group consisting of: halogen, -OH, -NH2、-CN、-NH(C1-C3Alkyl), -N (C)1-C3Alkyl radical)2。
In another preferred embodiment, Z is a substituted or unsubstituted phenyl.
In another preferred embodiment, Z is a substituted or unsubstituted 5-7 membered heterocyclic ring containing one N heteroatom.
In another preferred embodiment, the 5-7 membered heterocyclic ring containing one N heteroatom is N with a substituted or unsubstituted C attached1-C6Heterocyclic ring of alkyl.
In another preferred embodiment, each L is independently selected from: -CH ═ CH-, -CH2-CH2-, -NH-, or a combination thereof.
In another preferred embodiment, R2Is methyl or
Wherein m is 1, 2, 3, 4, or 5.
In another preferred embodiment, R3Is composed of
Wherein n is 1, 2, 3, 4, or 5.
In another preferred embodiment, m is 3.
In another preferred embodiment, n is 3.
In another preferred embodiment, R1Is H or methyl.
In another preferred embodiment, R3Is composed of
In another preferred embodiment, R1And R2Are the same.
In another preferred embodiment, R1And R2Are both methyl groups.
In another preferred embodiment, the compound of formula a includes the following compounds or pharmaceutically acceptable salts thereof:
in another preferred embodiment, the compound of formula a comprises one or more compounds selected from the group consisting of:
in another preferred embodiment, the transient receptor potential channel protein TRPA1 is human transient receptor potential channel protein TRPA 1.
In another preferred embodiment, the disease associated with transient receptor potential channel proteins is selected from the group consisting of: pain, inflammation, respiratory disorder, pruritus, urinary tract disorder, and inflammatory bowel disease.
In another preferred embodiment, the respiratory disorder is selected from the group consisting of: asthma, cough, chronic obstructive pulmonary disease.
In another preferred embodiment, the pharmaceutical composition comprises 0.001-99 wt%, preferably 0.1-90 wt%, more preferably 1-80 wt% of the compound of formula a, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, based on the total weight of the composition.
In another preferred embodiment, the pharmaceutical composition or formulation may further comprise other pharmaceutically active ingredients or pharmaceutically acceptable carriers.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising (a) a compound of formula 1 or a pharmaceutically acceptable salt thereof, and an optical isomer or a pharmaceutically acceptable salt thereof; (b) a compound of formula 2 or a pharmaceutically acceptable salt thereof, and optical isomers thereof or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier
In another preferred embodiment, the weight ratio of the component (a) to the component (b) is 1:20 to 20:1, preferably 1:10 to 10:1, more preferably 1:5 to 5: 1.
In another preferred embodiment, in said pharmaceutical composition, the total amount of components (a) and (b) is 0.001-99 wt%, preferably 0.1-90 wt%, more preferably 1-80 wt%, based on the total weight of the composition.
In another preferred embodiment, the pharmaceutical composition or formulation may further comprise other pharmaceutically active ingredients or pharmaceutically acceptable carriers.
In a third aspect of the invention, there is provided a kit comprising:
(1) a first container, and a first pharmaceutical composition located in the container, the first pharmaceutical composition containing a compound of formula 1 or a pharmaceutically acceptable salt thereof, and an optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
(2) a second container, and a second pharmaceutical composition in said container, said second pharmaceutical composition comprising a compound of formula 2, or a pharmaceutically acceptable salt thereof, and an optical isomer or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier;
and (3) optionally instructions for use.
In a fourth aspect of the present invention there is provided an in vitro non-therapeutic method of inhibiting the activity of a transient receptor potential channel protein TRPA1 by contacting the transient receptor potential channel protein with a compound of formula a, wherein the compound of formula a is as described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate or pharmaceutically acceptable salt thereof, thereby inhibiting the activity of the transient receptor potential channel protein.
In a fifth aspect of the present invention, there is provided a method for inhibiting transient receptor potential channel protein TRPA1, comprising the steps of: administering to a subject in need thereof a compound of formula a, wherein said compound of formula a is as described in the first aspect of the invention.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a graph showing the dose-response relationship of Compound 1 in inhibiting TRPA1 activity.
Detailed Description
The invention, after extensive and intensive research, unexpectedly discovers that a class of amide compounds with the structure shown as formula A can obviously inhibit the activity of TRPA1 for the first time. Experiments show that the compound of the formula A has a good inhibition effect on TRPA 1. The compound of formula A of the invention can be used for treating pain, inflammation, respiratory disorder, pruritus, urinary tract disorder, inflammatory bowel disease and the like related to TRPA1 target spot. On the basis of this, the present invention has been completed.
Term(s) for
The term "C1-C8 alkyl" refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
The term "C1-C3 alkyl" refers to straight or branched chain alkyl groups having 1-3 carbon atoms, such as methyl, ethyl, propyl, or the like.
The term "C1-C3Haloalkyl "refers to a halogen-substituted straight or branched chain alkyl group having 1 to 3 carbon atoms, such as halomethyl, haloethyl, halopropyl, haloisopropyl, or the like.
The term "C3-C8 cycloalkyl" refers to cycloalkyl groups having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like.
The term "C3-C6 cycloalkyl" refers to cycloalkyl groups having 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or the like.
The term "C5-C7 cycloalkyl" refers to cycloalkyl groups having 5-7 carbon atoms, such as cyclopentyl, cyclohexyl, or the like.
The term "5-7 membered heterocyclic ring" refers to a cyclic structure having one or more, preferably 1-3 heteroatoms, which ring may be saturated or unsaturated.
The term "halogen" refers to F, Cl, Br and I.
Active ingredient
As used herein, "compound of the present invention", or "compound of formula a", are used interchangeably and refer to a compound of formula a, or a racemate, a enantiomer, or a pharmaceutically acceptable salt thereof. It is to be understood that the term also includes mixtures of the above components.
The compound of the invention not only has an inhibiting effect on TRPA1, but also has a certain inhibiting effect on other members in a TRP family.
In the formula, each group is as defined above.
In the present invention, pharmaceutically acceptable salts of the compounds of formula a are also included. The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.
The compounds of formula a of the present invention can be prepared by methods well known to those skilled in the art, and the reaction parameters of the respective steps are not particularly limited. In addition, typical compounds of the present invention are also available in a commercially available manner.
As used herein, in the compound of formula a, if a chiral carbon atom is present, the chiral carbon atom may be in the R configuration, may also be in the S configuration, or a mixture of both.
Sinarelin, a SARS-COV drug, can be used for treating schizophrenia, but the compound is not available in the market as a human drug. Bupivacaine hydrochloride is an amide long-acting local anesthetic and is suitable for local infiltration anesthesia, peripheral nerve block and intravertebral block. The anesthesia time is 2-3 times longer than that of lidocaine hydrochloride, and the dispersivity is similar to that of lidocaine hydrochloride. Has little influence on circulation and respiration, no irritation to tissues, no generation of methemoglobin, no influence on cardiovascular function in common use amount, and can cause blood pressure reduction and heart rate reduction in large use amount. Has obvious blocking effect on beta-receptor. Levobupivacaine hydrochloride is an amide local anesthetic and is mainly used for surgical epidural anesthesia. The bupivacaine is an amide local anesthetic, has less accumulation in vivo and long action duration (can be maintained for 5 hours), and is a safer long-acting local anesthetic. Is mainly used for epidural stagnation anesthesia.
Transient receptor potential channel protein (TRPA1)
Transient receptor potential channel proteins (TRPA1) are a superfamily of proteins that are important cation channels present in cell membranes. The TRPA1 channel is found to be related to diseases such as pain, neuropathy and the like. In addition, TRPA1 has been demonstrated to be a target for the treatment of inflammation, respiratory disorders, pruritus, urinary tract infections and inflammatory bowel disease.
Use of
The present invention also provides a method of inhibiting transient receptor potential channel protein TRPA1, and a method of treating a disease associated with a transient receptor potential channel protein.
The compound of the formula A can be used for inhibiting TRPA1, and further preventing or treating diseases related to transient receptor potential channel protein.
In the present invention, examples of diseases associated with transient receptor potential channel proteins include (but are not limited to): pain, inflammation, respiratory disorder, pruritus, urinary tract disorder, and inflammatory bowel disease. Preferably, the respiratory disorder is selected from the group consisting of: asthma, cough, chronic obstructive pulmonary disease.
In one embodiment, the present invention provides an in vitro non-therapeutic method of inhibiting transient receptor potential channel protein TRPA1 activity comprising: for example, a transient receptor potential channel protein or a cell expressing the protein is contacted with a compound of formula a (or an optical isomer or racemate thereof, or a solvate or pharmaceutically acceptable salt thereof) in an in vitro culture system, thereby inhibiting the activity of the transient receptor potential channel protein.
The present invention also provides a method of inhibiting the transient receptor potential channel protein TRPA1, which may be therapeutic or non-therapeutic. Generally, the method comprises the steps of: administering to a subject in need thereof a compound of formula a of the present invention.
Preferably, the subject includes human and non-human mammals (rodents, rabbits, monkeys, domestic animals, dogs, cats, etc.).
Compositions and methods of administration
The present invention provides a composition for inhibiting transient receptor potential channel protein (TRPA1) activity. The composition includes (but is not limited to): pharmaceutical compositions, food compositions, dietary supplements, beverage compositions, and the like.
In the present invention, the pharmaceutical composition can be directly used for the treatment of diseases, for example, for the treatment of respiratory disorders.
The invention also provides a pharmaceutical composition comprising a safe and effective amount of a compound of the invention and a pharmaceutically acceptable carrier or excipient. Such vectors include (but are not limited to): saline, buffer, dextrose, water, glycerol, ethanol, powders, and combinations thereof. The pharmaceutical preparation should be compatible with the mode of administration.
In the case of pharmaceutical compositions, the compositions of the present invention may be prepared in the form of injections, for example, by conventional methods using physiological saline or aqueous solutions containing glucose and other adjuvants. Pharmaceutical compositions, such as tablets and capsules, can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under sterile conditions. The pharmaceutical combination of the present invention may also be formulated as a powder for inhalation by nebulization.
In addition, the transient receptor potential channel protein (TRPA1) inhibitors of the present invention may also be used with other therapeutic agents.
For the pharmaceutical compositions of the present invention, administration to a subject in need thereof (e.g., human and non-human mammals) can be by conventional means. Representative modes of administration include (but are not limited to): oral administration, injection, aerosol inhalation, etc.
The main advantages of the invention include:
(a) the compound of formula a of the present invention has a significant inhibitory effect on TRPA 1.
(b) The typical compound of formula A of the invention has excellent safety, little or no toxic and side effects.
(c) The compound of the formula A has good development and application prospects for treatment of various diseases related to the TRPA1 target.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Material
general procedure
IonWorks Barracuda (IWB) automated patch clamp assay: HEK293 cells stably expressing mTRPA1, DMEM medium containing 15g/mL of Blasticidin S HCl, 200g/mL of Hygromycin B and 10% FBS serum were placed in a T175 flask at 37 ℃ in 5% CO2Culturing in the incubator, removing the culture solution when the cell density reaches 80%, washing with Phosphate Buffer Solution (PBS) without calcium and magnesium, adding 3mL of Trypsin for digestion for 2 minutes, and adding 7mL of culture solution to stop digestion. Collecting cells into a 15mL centrifuge tube, centrifuging at 800 rpm for 3 minutes, removing supernatant, adding cells into an appropriate volume of extracellular fluid, and resuspending to control cell density at 2-3 × 106mL, and used for IWB experiments. Extracellular fluid formulation (in mM): 140NaCl,5KCl,1MgCl210HEPES,0.5EGTA,10Glucose (pH 7.4); intracellular fluid formulation (in mM): 140CsCl,10HEPES,5EGTA,0.1CaCl2,1MgCl2(pH 7.2). Amphotericin B and DM used on the same day of experimentSO was freshly prepared at 28mg/mL and then made up with intracellular fluid at a final concentration of 0.1 mg/mL.
The IWB experiment used a Population Patch Clamp (PPC) plate and the entire assay was automated by the instrument. Adding extracellular fluid into 384 holes of the PPC plate, adding intracellular fluid under the PPC plate (namely, inside the plenum), adding 6L of the intracellular fluid to perform a sealing test, and finally, replacing the intracellular fluid in the plenum with the intracellular fluid containing amphotericin B to punch sealed cells to form a whole cell recording mode. The TPRA1 current was recorded at a sampling frequency of 10kHz, cell clamping at 0mV, and a voltage stimulation command (channel protocol) as a ramp voltage of 300ms from-100 mV to +100mV, with voltage stimulation applied every 10s and mTRPA current induced by 300M AITC.
Data recording and current magnitude measurement derivation was done by IWB software (version 2.5.3, Molecular Devices Corporation, Union City, CA). Holes with a seal impedance below 20M Ω will not record data statistics. The raw current data was corrected for leakage by software, and the TRPA1 current amplitude was measured at +100 mV. Each PPC plate of the experiment will have a dose effect data of HC030031 as positive control, e.g. IC of HC03003150Value exceeding that of the IC obtained on each board50At 3 times the average value, retesting will be performed. Compound dose response curves and IC50Fitting calculations were performed by GraphPad Prism 5.02(GraphPad Software, San Diego, CA).
Example 1
The results are shown in table 1 below: the compounds 1, 2, 3 and 4 of the invention are all transient receptor potential channel protein (TRPA1) activity inhibitors, and the compounds 1, 2, 3 and 4 have obvious inhibition effect on the activity of TRPA 1.
TABLE 1
Example 2
Medicine box
Preparing a kit comprising:
(1) a first container, and a first pharmaceutical formulation (e.g., a tablet) located within the container, the formulation comprising the following active ingredients;
(2) a second container, and a first pharmaceutical formulation (e.g., a tablet) located within the container, the formulation comprising the following active ingredients;
and (3) instructions for use.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (2)
1. An in vitro non-therapeutic method for inhibiting the activity of a transient receptor potential channel protein TRPA1, characterized in that the transient receptor potential channel protein TRPA1 is contacted with sinaxelin represented by the following formula or a pharmaceutically acceptable salt thereof, thereby inhibiting the activity of the transient receptor potential channel protein,
2. the method according to claim 1, characterized in that said transient receptor potential channel protein TRPA1 is the human transient receptor potential channel protein TRPA 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011508784A (en) * | 2008-01-04 | 2011-03-17 | アボット・ラボラトリーズ | TRPA1 antagonist |
-
2016
- 2016-07-25 CN CN201610589481.3A patent/CN106214670B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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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