Application of alkylamine compound

Abstract

The invention relates to application of alkylamine compounds. Specifically, the invention provides an application of a compound shown as a formula I, or an optical isomer thereof, or a raceme thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, the compound, or the optical isomer thereof, or the raceme thereof, or the solvate thereof, or the pharmaceutically acceptable salt thereof are used for preparing a pharmaceutical composition or a preparation, and the pharmaceutical composition or the preparation is used for (a) inhibiting transient receptor potential channel protein; (b) treating diseases related to transient receptor potential channel protein, in the formula, each group is defined as in the specification. (I).

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry and pharmacotherapy, in particular to the use of a class of alkylamine compounds. BACKGROUND

[0002] In 1999, Jaquemar et al. first isolated an ankyrin-like protein in human lung fibroblasts, and in 2003, Story et al. found that an ankyrin protein called ANKTM1 was expressed in the dorsal root ganglion of mice, which was found to be a member of the TRP ion channel family, i.e. TRPA1, through sequence analysis. TRPA1 has 6 transmembrane proteins, both the N- and C-termini of which are intracellular, and the S5-S6 transmembrane domain hydrophilic region forms a pore. The specific structure is that there are at least 14 ankyrin repeat sequences at the N-terminus. TRPA1 is mainly distributed on the primary sensory neurons of the dorsal root nerve, trigeminal nerve and vagus nerve, and is expressed in both peptide- and non-peptide- sensitive neurons. In recent years, studies have shown that TRPA1 is also expressed on some non-neural cells, such as inner ear hair cells, intestinal chromaffin cells, vascular endothelial cells, dental pulp fibroblasts keratinocytes, islet cells, etc.

[0003] TRPA1 can be activated by a variety of chemicals. According to its activation mechanism, it can be divided into electrophilic agonists and non-electrophilic agonists. Most of the electrophilic agonists achieve the activation effect by covalent modification of the N-terminal cysteine residue of the TRPA1 channel. For example, allyl isothiocyanate (AITC) activates TRPA1 to cause pain by reversibly covalently binding to the N-terminal cysteine residue. Non-electrophilic agonists have a bidirectional regulation on the TRPA1 channel, i.e. low concentration shows an activation effect and high concentration shows an antagonistic effect. For example, menthol, apomorphine, nicotine, etc. According to the source of these stimulants, they can be divided into endogenous agonists and exogenous agonists. Most of the endogenous agonists are endogenous inflammatory mediators, such as oxidative stress and nitration stress products, H2O2, O3, NO, 4-hydroxy nonenoic acid (4-HNE), 4-ONE, 4-HHE, etc. Exogenous agonists include natural spicy components such as capsaicin, gingerol, carvacol, and environmental irritants such as propylene aldehyde, butenyl aldehyde, tear gas, and some general anesthetics such as isoflurane and desflurane. At the same time, TRPA1 can also be activated by noxious cold stimulation (<17 ℃) and mechanical stimulation.

[0004] Recent studies have found that TRPA1 channel is related to pain, neuropathy and other diseases. At present, domestic research is less, but foreign pharmaceutical companies have developed a series of pyrimidine dione TRPA1 inhibitors, and TRPA1 channel has become a research hotspot of new analgesics. At present, a variety of technical means including RNA interference, gene knockout, etc. have clearly defined the role of TRPA1 in pain perception. The phase 1 and phase 2 clinical trials of TRPA1 antagonists for acute and chronic pain are in progress to replace the traditional opioid analgesics. As a new target of analgesic drugs, TRPA1 will certainly open up a new research direction for analgesics.

[0005] The function and role of TRPA1 channel are still being further understood, and the latest research has found that its blockers have anti-depression and anti-anxiety effects. In addition, TRPA1 is also a target that has been proven to treat inflammation, respiratory disorders (asthma, cough, chronic obstructive pulmonary disease), itching related to oxidative stress, reduce urinary tract infections and inflammatory bowel disease, and major pharmaceutical companies are very active in this field. SUMMARY

[0006] The purpose of the present application is to provide the use of a class of compounds targeting TRP (especially TPRA1).

[0007] In a first aspect, the present application provides the use of a compound of formula I, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is used for the preparation of a pharmaceutical composition or a preparation for (a) inhibiting transient receptor potential channel proteins; (b) treating diseases related to transient receptor potential channel proteins: (I)

[0008] wherein: Ar is a substituted or unsubstituted C6-C20 aryl or a substituted or unsubstituted 5-12 membered heteroaryl;

[0009] R 1 and R 2 are connected to form a ring chain to form a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclopentyl, a substituted or unsubstituted cyclohexyl, a substituted or unsubstituted tetrahydropyran;

[0010] -X-Y- is an ester group, an amide group, -CH2O- or -CH2NH-;

[0011] Z is -OCH2CH2NEt2, -NEt2, piperidinyl, tetrahydropyrrolyl or ;

[0012] Unless otherwise specified, "substitution" refers to the substitution of one or more (preferably 1-3 hydrogen atoms) hydrogen atoms on a group by a substituent selected from the group consisting of: halogens, C1-C6 alkyl groups, C1-C4 haloalkyl groups, C3-C6 cycloalkyl groups, C6-C6 cycloalkyl groups, and C6-C6 cycloalkyl groups. 10 Aryl, benzyl, C1-C4 alkoxy, -OH, or -NH2;

[0013] The compound is selected from the following compounds:

[0014]

[0015] In another preferred embodiment, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier.

[0016] In another preferred embodiment, the pharmaceutical composition contains 0.001-99 wt%, more preferably 0.1-90 wt%, more preferably 1-80 wt% of a compound of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.

[0017] In another preferred embodiment, the dosage form of the pharmaceutical composition is an oral dosage form, an inhaler, or an injection.

[0018] In another preferred embodiment, the oral dosage form includes tablets, capsules, films, granules, etc., and also includes sustained-release or non-sustained-release dosage forms.

[0019] In another preferred embodiment, the transient receptor potential channel protein is TRPA1.

[0020] In another preferred embodiment, the diseases associated with the transient receptor potential channel protein TRPA1 are selected from the group consisting of: pain, inflammation, neuropathy, respiratory disorders, pruritus, urinary tract infection, or inflammatory bowel disease.

[0021] A second aspect of the present invention provides a method for in vitro non-therapeutic inhibition of transient receptor potential channel protein activity, the method comprising the steps of: contacting the transient receptor potential channel protein or cells expressing the protein with a compound of formula A, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, thereby inhibiting the activity of the transient receptor potential channel protein, wherein the compound of formula I is as described in the first aspect of the present invention.

[0022] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description Figure 1AIC50values for the inhibition of TRPA1 activity of compound 1 tested in automated patch clamp 50。 Figure 1B IC50values for the inhibition of TRPA1 activity of compound 4 tested in automated patch clamp 50。 DETAILED DESCRIPTION

[0023] The present inventors have made extensive and intensive studies, and for the first time, unexpectedly found that a class of compounds of formula I, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, can significantly inhibit the activity of TRPA1. Experiments show that the compound of formula I has a good inhibitory effect on TRPA1. The compound of formula I of the present application can be used for treating pain, inflammation, respiratory disorders, itching, urinary tract disorders, inflammatory bowel disease, etc. related to the TRPA1 target. On this basis, the present application is completed.

[0024] TERMS

[0025] As used herein, "R1", "R1", and "R 1 " have the same meaning. Other similar definitions have the same meaning.

[0026] As used herein, the terms "comprise", "include", "contain", and "have" are used interchangeably and mean that the composition includes the recited elements, but not excluding others.

[0027] As used herein, the term "halogen" means F, Cl, Br, and I.

[0028] As used herein, the term "C1-C4alkyl" means a straight or branched chain alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, or the like.

[0029] As used herein, the term "C1-C4alkoxy" means a straight or branched chain alkoxy group having 1-4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, or the like.

[0030] As used herein, the term "C3-C6cycloalkyl" means a cycloalkyl group having 3-16 carbon atoms, such as cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, or the like.

[0031] As used herein, the term "C1-C4haloalkyl" means a straight or branched chain alkyl-halogen resulting substituent having 1-4 carbon atoms, such as -CH2Cl, -CH2CH2Br, CH2CHCH2Cl, or the like.

[0032] As used herein, the term "C6-C10 aryl" refers to cyclic groups having aromatic structure, such as phenyl, naphthyl, or the like.

[0033] As used herein, the term "5-8 membered heteroaryl" refers to a monocyclic or fused polycyclic group having aromaticity with 5 to 8 members and having N, O or S in the ring system, such as pyrrolyl, pyridyl, furanyl, quinolyl, or the like.

[0034] As used herein, the term "halo" refers to one or more hydrogens on a group being replaced by a halogen.

[0035] Active ingredient

[0036] As used herein, "a compound of the present invention", or "a compound of Formula I" are used interchangeably to refer to a compound of Formula I, or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof. It is to be understood that the term also includes mixtures of the above components.

[0037] The compounds of the present invention not only have inhibitory effect on TRPA1, but also have certain inhibitory effect on other members of the TRP family.

[0038] The compounds of the present invention are compounds of Formula I, or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0039] (I)

[0040] In the formula, the definitions of the groups are as described above.

[0041] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicament. The pharmaceutically acceptable salt includes inorganic salts and organic salts. One preferred salt is a salt of a compound of the present invention with an acid. The acid suitable for salt formation includes, but is not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like, 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, benzenesulfonic acid, benzenesulfonic acid, and the like, and acidic amino acids such as aspartic acid, glutamic acid, and the like. One preferred salt is a salt of a compound of the present invention with a base. The base suitable for salt formation includes, but is not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, and the like, and organic bases such as aqueous ammonia, triethylamine, diethylamine, and the like.

[0042] Transient receptor potential channel proteins (TRPs)

[0043] Transient receptor potential channel proteins are a superfamily of important cation channel proteins present on the cell membrane. Transient receptor potential channels include several subfamilies, such as TRPC, TRPM, TRPV, TRPA, TRPML, and TRPP subfamilies.

[0044] It has been found that TRPA1 channel proteins are associated with pain, neuropathy, and other diseases. In addition, it has been confirmed that TRPA1 is a target for treating inflammation, respiratory disorders (e.g., asthma, cough, or chronic obstructive pulmonary disease), pruritus, urinary tract infection, and inflammatory bowel disease.

[0045] Use

[0046] The present application also provides a method for inhibiting transient receptor potential channel protein TRPA1, and a method for treating diseases associated with transient receptor potential channel proteins.

[0047] The above-mentioned compound of Formula I of the present application can be used for inhibiting TRPA1, and thus preventing or treating diseases associated with transient receptor potential channel proteins.

[0048] In the present application, examples of diseases associated with transient receptor potential channel proteins include, but are not limited to, pain, inflammation, respiratory disorders, pruritus, urinary tract disorders, and inflammatory bowel disease. Preferably, the respiratory disorder is selected from the group consisting of asthma, cough, and chronic obstructive pulmonary disease.

[0049] In one embodiment, the present application provides a method for inhibiting the activity of transient receptor potential channel protein TRPA1 in vitro, which can be non-therapeutic, comprising contacting transient receptor potential channel protein or a cell expressing the protein with a compound of Formula I (or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof), for example in an in vitro culture system, thereby inhibiting the activity of the transient receptor potential channel protein.

[0050] The present application also provides a method for inhibiting transient receptor potential channel protein TRPA1, which can be therapeutic or non-therapeutic. Generally, the method comprises the step of administering a compound of Formula I of the present application to a subject in need thereof.

[0051] Preferably, the subject includes humans and non-human mammals (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).

[0052] Compositions and methods of administration

[0053] The present application provides a composition for inhibiting the activity of transient receptor potential channel protein (TRPA1). The composition includes, but is not limited to, a pharmaceutical composition, a food composition, a dietary supplement, a beverage composition, etc.

[0054] The term "pharmaceutically acceptable carrier" refers to one or more compatible solid, semi-solid, liquid or gel fillers, excipients, or diluents, suitable for use in human or animal subjects and must be of sufficiently high purity and sufficiently low toxicity. By "compatible" is meant that the various components of the pharmaceutical composition are physically and chemically compatible, i.e., they will not interact in any manner that would substantially reduce the efficacy of the active ingredients or the pharmaceutical composition.

[0055] It is to be understood that the carrier in the present application is not particularly limited, and can be selected from materials commonly used in the art, or can be prepared by conventional methods, or can be purchased from the market. Examples of the pharmaceutically acceptable carrier include cellulose and its derivatives (e.g., methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween), wetting agents (e.g., sodium dodecyl sulfate), buffers, chelating agents, thickening agents, pH adjusting agents, transdermal enhancers, coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, bacteriostatic agents, pyrogen-free water, etc.

[0056] In addition to the active pharmaceutical ingredient, liquid dosage forms can include inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3- butanediol, dimethylformamide, and oils, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances, and the like.

[0057] In the present application, the dosage form of the pharmaceutical composition includes, but is not limited to, oral preparations, injections, and topical preparations. Representative examples include, but are not limited to, tablets, injections, infusions, ointments, gels, solutions, microspheres, and films.

[0058] The pharmaceutical preparation should be matched with the administration method. The pharmaceutical preparation of the present application can also be used with other synergistic therapeutic agents (including before, during, or after use). When using the pharmaceutical composition or preparation, a safe and effective amount of the drug is administered to the desired subject (e.g., a human or a non-human mammal), which is usually at least about 10 micrograms per kilogram of body weight, and in most cases no more than about 8 milligrams per kilogram of body weight, preferably the dose is about 10 micrograms per kilogram of body weight to about 1 milligram per kilogram of body weight. Of course, the specific dose should also take into account the administration route, the patient's health status, etc., which are within the skill of a skilled physician.

[0059] The main advantages of the present application include:

[0060] (a) The compound of formula I of the present application has significant inhibitory effect on transient receptor potential channel protein (especially TRPA1).

[0061] (b) The typical compound of formula I of the present application has excellent safety, with little or no toxic side effects.

[0062] (c) The compound of formula I of the present application has good development and application prospect for the treatment of various diseases related to TRPA1 target.

[0063] The present application is further illustrated by the following specific examples. It should be understood that these examples are intended to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods in the following examples, if not specified, are generally carried out according to the conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are by weight.

[0064] Experimental Section

[0065] Example 1: Synthesis of compound

[0066] Compound 1: 2-(2-(diethylamino)ethoxy)ethyl-1-phenylcyclopentanecarboxylate

[0067]

[0068] 1-phenylcyclopentanecarboxylic acid (400 mg, 2.10 mmol) was dissolved in toluene (10 mL), and thionyl chloride (2 mL) was added. The mixture was reacted at 80 °C for 2 hours, and then concentrated to give a yellow liquid which was directly used in the subsequent reaction. 2-(2-(diethylamino)ethoxy)ethanol (339 mg, 2.10 mmol), triethylamine (299 mg, 4.21 mmol) and the aforementioned yellow liquid were added to toluene (15 mL). The mixture was reacted at 80 °C for 2 hours. The mixture was concentrated, and then purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give a light yellow oil, 260 mg, yield 37.08%. 1H NMR (400 MHz, CDC13) δ 7.41 (d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 4.26 - 4.14 (m, 2H), 3.62 - 3.55 (m, 2H), 3.48 (t, J = 6.1 Hz, 2H), 2.76 - 2.67 (m, 2H), 2.66 - 2.54 (m, 6H), 1.94 (dd, J = 11.8, 7.9 Hz, 2H), 1.78 (dd, J = 9.6, 5.3 Hz, 4H), 1.07 (t, J = 7.1 Hz, 6H). HPLC: 99%; LC-MS (m / z): 334.4 [M+H] + .

[0069] Using a similar procedure to that used for the synthesis of Compound 1, the following compounds were obtained:

[0070] Compound 2: 2-(2-(Diethylamino)ethoxy)ethyl-l-phenylcyclopropane carboxylate

[0071]

[0072] HPLC: 99%; LC-MS (m / z): 306.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.39 - 7.23 (m, 5H), 4.16 - 4.07 (m, 2H), 3.56 - 3.47 (m, 2H), 3.42 (t, J = 5.9 Hz, 2H), 2.67 - 2.51 (m, 6H), 1.51 (q, J = 3.9 Hz, 2H), 1.22 (q, J = 3.9 Hz, 2H), 0.98 (t, J = 7.1 Hz, 6H).

[0073] Compound 3: 2-(2-(Diethylamino)ethoxy)ethyl-l-phenylcyclohexane carboxylate

[0074]

[0075] HPLC: 99%; LC-MS (m / z): 348.5 [M+H] + . 1H NMR (400 MHz, DMSO) δ 7.43 - 7.33 (m, 4H), 7.31 - 7.23 (m, 1H), 4.24 - 4.14 (m, 2H), 3.62 - 3.55 (m, 2H), 3.50 (s, 2H), 2.66 (s, 6H), 2.41 (d, J = 12.7 Hz, 2H), 1.75 - 1.56 (m, 5H), 1.44 (q, J = 12.1 Hz, 2H), 1.30 (dd, J = 15.5, 7.3 Hz, 1H), 1.02 (t, J = 6.6 Hz, 6H).

[0076] Compound 4: 2-(2-(Diethylamino)ethoxy)ethyl-4-phenyltetrahydro-2H-pyran-4- carboxylate

[0077]

[0078] HPLC: 99%; LC-MS (m / z): 350.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.43 - 7.35 (m, 4H), 7.34 - 7.27 (m, 1H), 4.24 - 4.16 (m, 2H), 3.89 - 3.80 (m, 2H), 3.59 - 3.52 (m, 2H), 3.47 (t, J = 11.1 Hz, 2H), 3.41 (t, J = 6.2 Hz, 2H), 2.54 - 2.40 (m, 8H), 1.95 - 1.81 (m, 2H), 0.95 (t, J = 7.1 Hz, 6H).

[0079] Compound 5: 2-(2-(Piperidin-l-yl)ethoxy)ethyl-l-phenylcyclopentane carboxylate

[0080]

[0081] HPLC: 99%; LC-MS (m / z): 346.6 [M+H] + . 1H NMR (400 MHz, DMSO) δ 7.40 - 7.30 (m, 4H), 7.29 - 7.22 (m, 1H), 4.16 - 4.08 (m, 2H), 3.53 - 3.48 (m, 2H), 3.42 (t, J = 5.9 Hz, 2H), 2.59 (dd, J = 11.2, 5.3 Hz, 2H), 2.36 (dd, J = 10.7, 4.8 Hz, 6H), 1.92 - 1.79 (m, 2H), 1.76 - 1.62 (m, 4H), 1.53 - 1.44 (m, 4H), 1.41 - 1.34 (m, 2H).

[0082] Compound 6: 2-(2-(pyrrolidin-1-yl)ethoxy)ethyl-1-phenylcyclopentanecarboxylate

[0083]

[0084] HPLC: 99%; LC-MS (m / z): 332.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.38 - 7.31 (m, 4H), 7.29 - 7.21 (m, 1H), 4.19 - 4.05 (m, 2H), 3.55 - 3.48 (m, 2H), 3.46 - 3.38 (m, 2H), 2.62 - 2.54 (m, 2H), 2.51 (dd, J = 12.0, 6.0 Hz, 2H), 2.42 (d, J = 6.1 Hz, 4H), 1.90 - 1.80 (m, 2H), 1.75 - 1.57 (m, 8H).

[0085] Compound 7: 2-(2-(diethylamino)ethoxy)ethyl-1-(thiophen-2-yl)cyclopentanecarboxylate

[0086]

[0087] HPLC: 99%; LC-MS (m / z): 340.3 [M+H] + . 1H NMR (400 MHz, CDC13) δ 7.22 (d, J = 4.6 Hz, 1H), 7.01 - 6.94 (m, 2H), 4.31 - 4.24 (m, 2H), 3.87 - 3.78 (m, 2H), 3.70 - 3.60 (m, 2H), 3.04 (dd, J = 13.5, 6.3 Hz, 6H), 2.69 - 2.50 (m, 2H), 2.22 - 2.07 (m, 2H), 1.78 (dd, J = 11.1, 6.0 Hz, 4H), 1.32 (dd, J = 14.3, 7.1 Hz, 6H).

[0088] Compound 8: 2-(2-(diethylamino)ethoxy)ethyl-l-(pyridin-2-yl)cyclohexanecarboxylate

[0089]

[0090] HPLC: 99%; LC-MS (m / z): 349.6 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.64 - 8.56 (m, 1H), 7.67 (td, J = 7.8, 1.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.17 (dd, J = 7.4, 4.8 Hz, 1H), 4.33 - 4.27 (m, 2H), 3.69 - 3.61 (m, 2H), 3.56 (t, J = 5.9 Hz, 2H), 2.68 (dt, J = 14.0, 6.3 Hz, 6H), 2.45 (t, J = 15.8 Hz, 2H), 1.92 (dd, J = 17.7, 7.5 Hz, 2H), 1.78 - 1.63 (m, 2H), 1.63 - 1.49 (m, 2H), 1.46 - 1.23 (m, 2H), 1.09 (t, J = 7.1 Hz, 6H).

[0091] Compound 9: 2-(l-methylpyrrolidin-2-yl)ethyl-l-phenylcyclopentanecarboxylate

[0092]

[0093] HPLC: 99%; LC-MS (m / z): 302.4 [M+H]+ . 1 H NMR (400 MHz, DMSO) δ 7.35 (d, J =3.8 Hz, 4H), 7.29 – 7.23 (m, 1H), 4.08 – 3.97 (m, 2H), 2.93 – 2.84 (m, 1H),2.62 – 2.54 (m, 2H), 2.11 (s, 3H), 1.97 (q, J = 8.8 Hz, 1H), 1.91 – 1.77 (m,4H), 1.68 (tdd, J = 16.5, 8.0, 3.7 Hz, 5H), 1.59 – 1.51 (m, 2H), 1.41 – 1.22(m, 2H).

[0094] Compound 10: 1-phenylcyclopentane-1-carboxylic acid-2-(diethylamino)ethyl ester

[0095]

[0096] HPLC: 99%; LC-MS (m / z): 290.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J= 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 4.14 (t, J= 6.1 Hz, 2H), 2.67 (dt, J = 12.3, 6.1 Hz, 4H), 2.51 (q, J = 7.1 Hz, 4H),1.94 (dd, J = 12.1, 8.1 Hz, 2H), 1.87 – 1.69 (m, 4H), 1.00 (t, J = 7.1 Hz,6H).

[0097] Compound 11: N-(2-(2-(diethylamino)ethoxy)ethyl)-1-phenylcyclopentane-1-carboxamide

[0098]

[0099] 1-phenylcyclopentane-1-carboxylic acid (590 mg, 3.12 mmol), 2-(2-aminoethoxy)-N,N-diethylethan-1-amine (500 mg, 3.12 mmol, ref. WO2013018929), 1-hydroxybenzotriazole (950 mg, 6.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.24 mmol) and diisopropylethylamine (1.6 g, 12.48 mmol) were dissolved in DMF (30 mL) and the reaction was left to proceed at room temperature overnight. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated and the product was isolated by column chromatography (dichloromethane:methanol = 12:1) to give 370 mg of a brown oil, yield: 36%. 1 HNMR (400 MHz, DMSO) δ 7.42 (t, J = 5.3 Hz, 1H), 7.33 (dt, J = 14.9, 7.5 Hz,4H), 7.21 (t, J = 6.9 Hz, 1H), 3.43 – 3.27 (m, 4H), 3.14 (q, J = 5.8 Hz, 2H),2.60 – 2.50 (m, 2H), 2.46 (q, J = 7.0 Hz, 6H), 1.78 (dd, J = 13.1, 5.7 Hz,2H), 1.70 – 1.52 (m, 4H), 0.94 (t, J = 7.1 Hz, 6H). HPLC:99%; LC-MS (m / z): 333.5 [M+H] + .

[0100] Compound 12: N,N-diethyl-2-(2-((1-phenylcyclopentyl)methyl)amino)ethoxy)ethan-1- amine

[0101]

[0102] Compound 11 (370 mg, 1.11 mmol) was dissolved in toluene (20 mL) and 70% red aluminium in toluene (224 mg, 1.11 mmol) was added. The reaction was left to proceed at reflux overnight. After cooling to room temperature, it was washed with water and extracted with ethyl acetate. The product was isolated by column chromatography (eluent dichloromethane:methanol = 10:1) to give 50 mg of a yellowish oil, yield: 14%. 1H NMR (400 MHz, DMSO) δ 7.31 (d, J = 4.3 Hz, 4H), 7.22 - 7.16 (m, 1H), 3.35 - 3.30 (m, 4H), 2.64 (s, 2H), 2.51 (d, J = 5.5 Hz, 2H), 2.47 - 2.37 (m, 6H), 2.00 (dd, J = 10.7, 5.6 Hz, 2H), 1.84 - 1.56 (m, 6H), 0.91 (t, J = 7.1 Hz, 6H). HPLC: 99%; LC-MS (m / z): 319.6 [M+H] + .

[0103] Compound 13 was obtained using a similar method to that used for the synthesis of compound 12:

[0104] Compound 13: N,N-diethyl-2-(2-((l-phenylcyclopentyl)methoxy)ethoxy)ethan-l- amine

[0105]

[0106] HPLC: 99%; LC-MS (m / z): 320.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.34 (dt, J = 15.1, 7.6 Hz, 4H), 7.20 (dd, J = 15.9, 9.0 Hz, 1H), 3.57 (s, 2H), 3.47 (dd, J = 12.0, 6.6 Hz, 8H), 2.81 (s, 4H), 2.10 - 1.94 (m, 2H), 1.90 - 1.77 (m, 2H), 1.69 (tt, J = 23.6, 11.8 Hz, 4H), 1.09 (s, 6H).

[0107] Example 2

[0108] Test experiment for inhibitory activity of transient receptor potential channel protein TRPA1

[0109] In this example, the compound (1-13) prepared in Example 1 was subjected to an activity test. The method was as follows:

[0110] Cell culture and handling: HEK293 (human embryonic kidney 293) cells stably expressing mouse-TRPA1 channels were cultured in 35 mm diameter cell culture dishes in a 37°C, 5% CO2 incubator and passaged every 48 hours at a 1 :3 ratio. The culture medium was composed of 90% DMEM (Invitrogen), 10% fetal bovine serum (Gibco), 2 mM 1% P / S L-Glutamine (Invitrogen), 15 ug / mL Blastcidine (Invitrogen) and 200 μg / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated and the cells were rinsed once with extracellular solution before the addition of a 0.25% Trypsin-EDTA (Invitrogen) solution for 3-5 minutes at room temperature. The trypsin solution was aspirated and the cells were resuspended in extracellular solution before being transferred to the experimental dish for electrophysiological recordings. The extracellular solution was composed of (mM): 140 NaCl; 5 KCl; 0.5 EGTA; 1 MgCl2; 10 Glu; 10 HEPES pH=7.4 (with NaOH).

[0111] Manual patch clamp electrophysiological recording procedure: HEK293 cells stably expressing mTRPA1 channels were recorded using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode capillaries (BF150-86-10, Sutter) using a micropipette puller and had a tip resistance of 2-5 MΩ after being filled with internal solution. The glass microelectrode was inserted into the headstage of the amplifier and connected to the patch clamp amplifier. The voltage clamp and data recording were controlled and recorded by a computer using the pClamp 10 software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at 0 mV for 50 ms, given a hyperpolarizing voltage to -100 mV for 20 ms, then depolarized to +100 mV for 300 ms to induce the TRPA1 current, and then repolarized to 0 mV for 50 ms after maintaining at +100 mV for 20 ms. This voltage stimulus was given every 2 s, and after the mTRPA1 current was stable (1 minute), the drug administration process began. Each test concentration of compound was given for 20 seconds, and at least 3 cells were tested for each concentration (n≥3).

[0112] Data analysis was performed using pClamp 10, GraphPad Prism 5 and Excel software. The inhibition of mTRPA1 current by different concentrations of compounds was calculated using the following formula: Inhibition% = [1 - (I / Io)] x 100%. Where Inhibition% represents the inhibition percentage of mTRPA1 current by the compound, I and Io represent the amplitude of mTRPA1 current after and before drug application, respectively. Compound IC 50 was calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 - X)*HillSlope)) Where X is the Log value of the test concentration of the sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0113] The quality control of experimental data met the following indicators: whole cell seal impedance > 1 GΩ; series resistance > 10 MΩ, compensation > 80%; TRPA1 current amplitude had no obvious spontaneous decay before drug application; the inhibition rate of 10 μM HC-030031, a positive inhibitor, on mTRPA1 channel was greater than 90%.

[0114] Experimental results

[0115] The IC 50 of the compounds of the present application was tested by manual patch clamp detection, and the activity data is shown in Table 1, and the dose-effect relationship of inhibition of TRPA1 activity of some representative compounds is shown in Figure 1.

[0116] Table 1. Inhibition activity data (IC 50 , μM) of TRPA1

[0117] Compound No. IC 50 , μM]]> Compound No. IC 50 , μM]]> Compound No. Compound No. IC 50 , μM]]> 1 ++++ 6 ++ 11 ++ 2 ++ 7 +++ 12 ++ 3 ++++ 8 ++ 13 ++ 4 ++++ 9 +++ 5 +++ 10 ++

[0118] Where activity: IC 50 <10 uM: +++; 40% ≤ inhibition rate < 50% @ 10 uM: ++; 10% ≤ inhibition rate < 40% @ 10 uM: +.

[0119] The results show that the compounds of the present application all exhibit strong TRPA1 inhibition activity.

[0120] All documents referred to in the present application are incorporated herein by reference as if each were individually incorporated. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that embodiments can be practiced without the specific details that are set forth herein. Further, it should be noted that, in this application, "exemplary" or "for example" is used on a purely illustrative basis to aid the reader in understanding the application. Any process steps, or sequences of steps, or examples, or embodiments, or materials, or components, or compounds, or elements described herein are understood to be illustrative only and not limiting.

Claims

1. Use of a compound of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, For use in the preparation of pharmaceutical compositions or formulations for (a) inhibiting transient receptor potential channel proteins; (b) treating diseases associated with transient receptor potential channel proteins: (I) Specifically, the compound of formula I is selected from the following group:

2. The use as described in claim 1, characterized in that, The pharmaceutical composition comprises a pharmaceutically acceptable carrier.

3. The use as described in claim 1, characterized in that, The pharmaceutical composition contains 0.001-99 wt% of a compound of formula I, based on the total weight of the composition.

4. The use as described in claim 1, characterized in that, The pharmaceutical composition contains 0.1-90 wt% of a compound of formula I, based on the total weight of the composition.

5. The use as described in claim 1, characterized in that, The pharmaceutical composition contains 1-80 wt% of a compound of formula I, based on the total weight of the composition.

6. The use as described in claim 1, characterized in that, The dosage form of the pharmaceutical composition is oral, inhaled, or injected.

7. The use as described in claim 6, characterized in that, The oral dosage forms include tablets, capsules, films, granules, etc., and also include sustained-release or non-sustained-release dosage forms.

8. The use as described in claim 1, characterized in that, The transient receptor potential channel protein mentioned is TRPA1.

9. The use as described in claim 1, characterized in that, The diseases associated with transient receptor potential channel proteins are selected from the following group: pain, inflammation, neuropathy, respiratory disorders, pruritus, urinary tract infection, or inflammatory bowel disease.

10. A method for in vitro, non-therapeutic inhibition of transient receptor potential channel protein activity, characterized in that, Contacting a transient receptor potential channel protein or a cell expressing the protein with a compound of formula I, or an optical isomer thereof, a racemic mixture thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, thereby inhibiting the activity of the transient receptor potential channel protein, wherein the compound of formula I is as described in claim 1.

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