CN111574432A - Soluble epoxy hydrolase and gamma-aminobutyric acid dual inhibitor and application thereof - Google Patents

Soluble epoxy hydrolase and gamma-aminobutyric acid dual inhibitor and application thereof Download PDF

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CN111574432A
CN111574432A CN202010556427.5A CN202010556427A CN111574432A CN 111574432 A CN111574432 A CN 111574432A CN 202010556427 A CN202010556427 A CN 202010556427A CN 111574432 A CN111574432 A CN 111574432A
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gamma
aminobutyric acid
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童成亮
徐奎
王陈
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ANHUI HEAL STAR PHARMACEUTICAL Co.,Ltd.
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Anhui Yixinming Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

The invention discloses a soluble epoxy hydrolase and gamma-aminobutyric acid dual inhibitor of formula (I) and pharmaceutically acceptable salts thereof, wherein R is1Selected from-H or-F or-Cl or-Br or-CN or-NO2；R2Is selected from-CF3or-OCF3or-CN or-NO2. The compounds of the invention and their pharmaceutically acceptable salts are useful for relieving pain and treating or preventing neuropathic pain.

Description

Soluble epoxy hydrolase and gamma-aminobutyric acid dual inhibitor and application thereof
One, the technical field
The invention relates to the field of pharmaceutical chemistry, and particularly relates to a soluble epoxy hydrolase and gamma-aminobutyric acid dual inhibitor and application thereof.
Second, background Art
In the past decades, pain has been a medical problem to be solved, which places a burden on the whole society and also severely reduces the quality of life of people. Pain is a complex signaling process resulting from the damage of harmful substances and the release of inflammatory mediators, such as cytokines, ions, bradykinin, prostaglandins, leukotrienes, etc., which act directly on pain receptors and drive action potentials to give a sensation of pain. Pain is generally a signal to avoid further injury. While many of these methods currently provide pain relief, most of these methods have side effects of dose-dependent or limited use. Therefore, new therapies are needed to treat pain.
In 2011, PAIN, an official journal of IASP, published a new definition of Neuropathic PAIN (NPP): pain, which is directly caused by injury or disease of the somatosensory nervous system, can be secondary to a variety of diseases or injuries, such as stroke, diabetes, and the like. NPP is one of the most difficult diseases to treat at present, and imposes a great burden on the society as well as on the life of individuals. Therefore, there is an urgent need to develop new methods for treating neuropathic pain.
Preliminary studies on the effect of potent soluble epoxy hydrolase (sEH) inhibitors in neuropathy were aimed at comparing COX levels with inflammatory pain in a pain model. Inceoglu et al [ Proceedings of the national academy of Sciences of the United States of America,2008,105(48): 18901-18906 ] found that sEH inhibition could block diabetic neuropathy in a chronic pain model, and therefore it was proposed as a negative control experimental model. This is an exciting matter, since most NSAIDs that block COX have little effect on neuropathic pain [ European Journal of Pharmacology,2013,700(1-3): 93-101 ]. Inceoglu [ Proc NatlAcad Sci U S A,2012,109(28): 11390-11395 ] et al explore the effect of sEH inhibitors on diabetic neuropathy in preclinical models, revealing that the dose-dependent improvement of sEH inhibitors on the mechanical pain threshold, and that sEH inhibitors are superior to standard treatment of gabapentin. This anti-hyperalgesia is not associated with changes in glucose tolerance, insulin resistance and glucose-stimulated insulin secretion. Wagner et al [ Behavioural Brain Research,2017,326: 69-76 ] further investigated the effects of sEH inhibitors in the type I diabetes model of mice in the early autumn field. sEH inhibitors were found to be effective against mouse diabetic neuropathy in studies modeled in oka mice, and sEH activity correlated with the severity of the disease. Guedes A et al [ Aquine Veterinary Journal,2017,49(3): 345-351 ] found that sEH inhibitors were more effective than the previous standard treatment methods in the study of treating severe equisetum, and that sEH inhibitors continued to succeed as a method of treating this disease. It can thus be concluded that sEH inhibitors may be one of the effective strategies for treating neuropathic pain.
The prior technical literature on the research of epoxide hydrolase inhibitors:
urea inhibitors (j.med.chem.mcelroy jm020269o supporting Info page 1-39), CN106163521, CN 101304737: the urea inhibitor is much researched in recent years, the action mechanism is that carbonyl oxygen in urea is combined with Tyr381 and Tyr465 in EH through hydrogen bonds, the carbonyl oxygen interacts with Gln382 to stabilize the negative charge of epoxide, and Asp333 at the carbonyl end can also receive the hydrogen bond of an enzyme inhibitor and then jointly act. However, when the groups attached to the left and right of the urea pharmacophore are different, their inhibitory effects are also different. Urea inhibitors can therefore be classified according to the difference between the left and right groups as follows:
1) cycloparaffin-urea inhibitors (Annu Rev Pharmacol Toxicol, 2005, 45: 311 to 333, BiolChem, 2000, 15: 265 to 275);
2) adamantane-urea inhibitors (Bioorganic & Medicinal Chemistry Letters 19(2009) 1784-1789, Protein Sci, 2006, 15: 58-64, J M ed Chem, 2007, 50: 5217-5226), CN 102464631;
3) aryl-urea inhibitors (Bioorganic & Medicinal Chemistry Letters, 2006, 16: 5773-5777, J Med Chem, 2010, 40: 222 to 238.)
4) Peptidyl-urea inhibitors (Adv Drug Deliv Rev, 2001, 46: 3 to 26)
5) Piperidine-urea inhibitors (Bioorganic & Medicinal Chemistry Letters, 2010, 20: 571-575, Bioorganic & Medicinal Chemistry Letters, 2009, 19: 5314-5320.)
6) Spiro-urea inhibitors (Bioorganic Chemistry 80(2018)655 to 667)
Amide inhibitors: the amide inhibitors and the urea inhibitors have similarities and differences on main structures, but when the main structures of the amide inhibitors and the urea inhibitors are respectively subjected to bilateral symmetry modification and asymmetric modification, the biological activity is obviously changed.
1) Adamantane-amide inhibitors (CN102664631), (J M ed Chem, 2007, 50: 3825 to 3840)
2) Piperidine-amide inhibitors (Bioorganic & Medicinal Chemistry Letters, 2009, 19: 2354 to 2359)
The epoxide hydrolase inhibitor has the following pharmacological effects: antiinflammatory, kidney protecting, nerve protecting, myocardium protecting, cardiopulmonary function protecting, analgesic, vasodilating, and arteriosclerosis preventing effects. According to incomplete statistics, the medicines which are commercialized at present comprise DCU, AUDA, TPPU and the like; but has some disadvantages of toxic and side effects or poor oral administration, which motivates people to further research on the medicine. The research on water solubility, stability, oral property and the like is carried out, and a rapid, efficient and selective inhibitor is expected to be found, so that the effect of treating related diseases is better.
Painful diabetic peripheral neuropathy is a type of diabetic peripheral neuropathy. It is often seen in diabetic patients with poor glycemic control, or in patients with sudden blood glucose fluctuations, such as ketoacidosis. The clinical manifestations are a rapid and marked decrease in body weight, with peripheral nerve lesions dominated by distal, with the main symptoms being pain, burning and needling sensations.
It is estimated that neuropathic pain affects 7-10% of the general population, greatly affecting people's daily functions and quality of life.
Various alternatives are available for treating pain. Examples include nonsteroidal anti-inflammatory drugs ((NSAIDs) or narcotic analgesics (e.g., opioids), however, the use of nonsteroidal anti-inflammatory drugs causes adverse side effects such as gastrointestinal injury or renal disease, and the use of narcotic analgesics causes adverse side effects such as constipation, drowsiness, nausea, or vomiting.
In contrast, neuropathic pain is treated by the use of anticonvulsants, such as gabapentin or pregabalin, and the frequency of occurrence of central nervous system side effects such as dizziness, nausea or vomiting is high. Therefore, new analgesics and therapeutic agents for neuropathic pain are in demand.
With the development of pharmacology, the action and mechanism of human soluble epoxide hydrolase is being discovered and elucidated, and the rationality and effectiveness of inhibitors as analgesics, particularly neuropathic pain medications, is further demonstrated. As research advances, more and more human soluble epoxide hydrolase inhibitors will be designed and synthesized, and none of these prior art documents describes the skillful docking derivatives of pregabalin with urea epoxide hydrolase of the present invention, and suggest the efficacy of the compounds of the present invention as drugs. Therefore, we have developed such products that will likely provide an alternative pathway to the treatment of analgesics, particularly neuropathic pain medications, and inflammatory pain related disorders.
Meanwhile, the development of the central nervous system drug is just like a black box, and it is difficult to judge what will be finally surprised.
Third, the invention
The object to be achieved by the invention is:
the invention provides outstanding compounds for treating or preventing various types of pain or neuropathic pain and pharmaceutical applications thereof.
The means for achieving the purpose are as follows:
the present inventors have conducted intensive studies to achieve the above object. As a result, we have found a soluble double inhibitor of epoxyhydrolase and gamma-aminobutyric acid which is shown to improve various types of pain or neuropathic pain, thereby completing the present invention.
Specifically, the present invention is summarized as follows:
(1) a dual soluble epoxyhydrolase and gamma-aminobutyric acid inhibitor represented by formula (I) and pharmaceutically acceptable salts thereof:
Figure BDA0002544471340000041
wherein: r1Selected from-H or-F or-Cl or-Br or-CN or-NO2；R2Is selected from-CF3or-OCF3or-CN or-NO2。
(2) A dual soluble epoxyhydrolase and gamma-aminobutyric acid inhibitor according to (1) and pharmaceutically acceptable salts thereof, wherein R1is-H or-F or-Cl, R2is-CF3or-OCF3。
(3) A dual soluble epoxyhydrolase and gamma-aminobutyric acid inhibitor according to (1) or (2) and pharmaceutically acceptable salts thereof, wherein the compound preferably has the following structure:
Figure BDA0002544471340000051
(4) a soluble dual inhibitor of epoxy hydrolase and gamma-aminobutyric acid and its pharmaceutically acceptable salt according to (1) or (2) or (3), wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulfate, nitrate, phosphate, formate, acetate, propionate, oxalate, malonate, butyrate, lactate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, maleate, benzoate, succinate, picrate, tartaric acid, citrate, fumarate.
(5) A pharmaceutical composition comprising a soluble epoxyhydrolase and a gamma-aminobutyric acid dual inhibitor according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
(6) An analgesic agent comprising a soluble epoxyhydrolase and gamma-aminobutyric acid dual inhibitor according to any one of (1) to (5) and a pharmaceutically acceptable salt thereof.
(7) A therapeutic or prophylactic agent for neuropathic pain comprising a soluble epoxyhydrolase and gamma-aminobutyric acid dual inhibitor according to any one of (1) to (5) and a pharmaceutically acceptable salt thereof.
(8) A therapeutic or prophylactic agent for inflammatory pain, which comprises a soluble epoxyhydrolase and gamma-aminobutyric acid dual inhibitor according to any one of (1) to (5) and a pharmaceutically acceptable salt thereof.
(9) Use of a dual inhibitor of soluble epoxyhydrolase and gamma-aminobutyric acid according to any one of (1) to (5) and pharmaceutically acceptable salts thereof for the manufacture of analgesics.
(10) Use of a dual inhibitor of soluble epoxyhydrolase and gamma-aminobutyric acid according to any one of (1) to (5) and a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for neuropathic pain
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The key points of the invention are as follows:
1) the human soluble epoxide hydrolase urea inhibitor and pregabalin form a multi-target twin drug, can obviously improve the analgesic effect, and can be used for preparing the drug for treating neuropathic pain;
2) stable chemical property and moderate water solubility, increases the water solubility of the urea inhibitor and has good drug property.
Fourth, detailed description of the invention
The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.
Example 1(S) -1- (1- (3- (aminomethyl) -5-methylhexanoyl) piperidin-4-yl) -3- (3-fluoro-4- (trifluoromethoxy) phenyl) urea (Compound I)1) Synthesis of (2)
Figure BDA0002544471340000061
The preparation process comprises the following reaction flows:
Figure BDA0002544471340000071
1. step 1
Adding S (+) vigabatrin (24g, 0.15mol), dioxane 170ml and deionized water 170ml into a 500ml three-neck flask in sequence, adding sodium hydroxide (18g, 0.45mol) under stirring at room temperature, stirring for 5min after the completion, adding 50ml dioxane solution of BOC anhydride (43.6g, 0.2mol), stirring the obtained mixed solution for 1.5h at room temperature, concentrating under reduced pressure to remove most dioxane after TLC identification reaction is completed, extracting residues with diethyl ether (3 x 100ml), removing an organic phase, adjusting pH of an aqueous layer to 1-2 with 10% citric acid aqueous solution, standing for 20min to separate out a large amount of white solid, filtering, washing the solid with a proper amount of water, and drying under vacuum at 55-60 ℃ for 4h to obtain 33.6g of white solid powder with the yield of 86%, wherein the HPLC content is 97.2%, and the white solid powder is directly used for the next reaction.
2. Step 2
Adding 3-fluoro-4- (trifluoromethoxy) aniline (68g, 0.35mol), toluene (400ml) and 31ml of pyridine into a 1000ml reaction kettle, stirring and dissolving, cooling to-5-0 ℃, dropwise adding 120ml of toluene solution of solid phosgene (60g, 0.2mol), keeping the temperature at-5-0 ℃ and stirring for 1.5h after the dropwise adding is finished, cooling to-10 ℃ after TLC (ethyl acetate-petroleum ether ═ 1: 10) identification reaction is finished, adding 4-aminopiperidine-1-carboxylic acid tert-butyl ester (80g, 0.4mol) in batches, detecting the pH of the reaction system during the adding process, keeping the pH at 8-9, adding a proper amount of pyridine if the pH is lower, keeping the temperature and reacting for 0.5h, heating to room temperature and stirring for 3h, after TLC (ethyl acetate-petroleum ether ═ 1: 10) identification reaction is finished, adding cold water 200ml, stirring for 20min, standing for layering, extracting water layer with toluene (3 × 200ml), combining organic layers, drying over anhydrous magnesium sulfate, and concentrating under reduced pressure to dryness for use in the next step.
3. Step 3
450ml of dioxane and 45ml of 6N hydrochloric acid solution are added to the product of the step 2, the reaction mixture is stirred at room temperature for 1.5h, and TLC identification reaction [ developing agent: ethyl acetate: and (3) after the reaction is finished, adding 300ml of diethyl ether, stirring for 1h, filtering, washing the solid with a proper amount of diethyl ether, and drying in vacuum at 35-40 ℃ for 6h to obtain 76.5g of white solid powder, wherein the total yield of the two steps is 68%, the HPLC content is 96.9%, and the white solid powder is directly used for the next reaction.
4. Step 4
Dissolving the product of the step 3 (32g, 0.1mol) and the product of the step 1 (31g, 0.12mol) in 300ml of dichloromethane, adding DCC (27g, 0.13mol) and DMAP (5g) under stirring, stirring for 15h at room temperature, filtering to remove insoluble DCHU, concentrating under reduced pressure to dryness, dissolving the product in toluene (300ml), adding water, washing with saturated sodium bicarbonate solution (3X 50ml), washing with saturated sodium chloride solution (50 ml), drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain 41g of white-like solid powder, wherein the yield is 73%, and the HPLC content is 94.3%, and directly using the white-like solid powder in the next reaction.
5. Step 5
Step 4, adding 410ml of dioxane and 12ml of 6N hydrochloric acid solution, stirring the reaction mixture at room temperature for 2h, and identifying the reaction by TLC [ developing agent: ethyl acetate: methanol 10:1], after the reaction was completed, 350ml of isopropyl ether was added, stirred for 1h, filtered, the solid was washed with an appropriate amount of isopropyl ether, vacuum-dried at 55 ℃ to 60 ℃ for 4h, and the obtained solid was recrystallized from acetonitrile to obtain 27.5g of a white crystalline solid powder, yield 81.1%, HPLC content 98.7%.
Figure BDA0002544471340000091
1H-NMR(500MHz,CDCl3/TMS，ppm):
8.53(s，1H)；7.84(s，1H)；7.33(d，J＝7.8Hz，1H)；7.01(d，J＝7.8Hz，1H)；6.45(s，1H)；3.68(m，1H)；3.52～3.59(t，J＝6.3Hz，4H)；1.76～2.04(t，J＝6.3Hz，4H)；1.99～2.31(d，J＝7.8Hz，2H)；1.66(m，1H)；2.46～2.72(t，J＝6.3Hz，2H)；1.37(t，J＝6.3Hz，2H)；1.74(m，1H)；0.93(s，6H)。
MS：m/z(M+H+)463.5。
Example 2(S) -1- (1- (3- (aminomethyl) -5-methylhexanoyl) piperidin-4-yl) -3- (3-fluoro-4- (trifluoromethyl) phenyl) urea (Compound I)2) Synthesis of (2)
Figure BDA0002544471340000092
Referring to example 1, wherein 3-fluoro-4- (trifluoromethoxy) aniline was replaced with 3-fluoro-4- (trifluoromethyl) aniline in step 2, Compound I was conveniently prepared27.6g, overall yield (from stage 2) 33.6%, HPLC content 98.2%.
Figure BDA0002544471340000093
1H-NMR(500MHz,CDCl3/TMS，ppm):
8.54(s，1H)；7.85(s，1H)；7.33(d，J＝7.8Hz，1H)；7.02(d，J＝7.8Hz，1H)；6.44(s，1H)；3.68(m，1H)；3.50～3.58(t，J＝6.3Hz，4H)；1.77～2.06(t，J＝6.3Hz，4H)；1.99～2.33(d，J＝7.8Hz，2H)；1.65(m，1H)；2.43～2.70(t，J＝6.3Hz，2H)；1.35(t，J＝6.3Hz，2H)；1.71(m，1H)；0.95(s，6H)。
MS：m/z(M+H+)447.5。
Example 3(S) -1- (1- (3- (aminomethyl) -5-methylhexanoyl) piperidin-4-yl) -3- (4- (trifluoromethoxy) phenyl) urea (Compound I)3) Synthesis of (2)
Figure BDA0002544471340000101
With reference to example 1, wherein 3-fluoro-4- (trifluoromethoxy) aniline was replaced with 4-trifluoromethylaniline in step 2, Compound I was conveniently prepared36.1g, overall yield (from stage 2) 38.2%, HPLC content 97.8%.
Figure BDA0002544471340000102
1H-NMR(500MHz,CDCl3/TMS，ppm):
8.56(s，1H)；7.28(d，J＝7.8Hz，2H)；6.87(d，J＝7.8Hz，2H)；6.53(s，1H)；3.70(m，1H)；3.53～3.62(t，J＝6.3Hz，4H)；1.79～2.08(t，J＝6.3Hz，4H)；1.94～2.30(d，J＝7.8Hz，2H)；1.65(m，1H)；2.41～2.74(t，J＝6.3Hz，2H)；1.37(t，J＝6.3Hz，2H)；1.72(m，1H)；0.94(s，6H)。
MS：m/z(M+H+)445.3。
Example 4(S) -1- (1- (3- (aminomethyl) -5-methylhexanoyl) piperidin-4-yl) -3- (3-chloro-4- (trifluoromethoxy) phenyl) urea (R-methyl-ethyl-methyl-phenyl)Compound I4) Synthesis of (2)
Figure BDA0002544471340000111
Referring to example 1, wherein 3-fluoro-4- (trifluoromethoxy) aniline was replaced with 3-chloro-4- (trifluoromethyl) aniline in step 2, Compound I was conveniently prepared43.7g, overall yield (from stage 2) 29.3%, HPLC content 99.1%.
Figure BDA0002544471340000112
1H-NMR(500MHz,CDCl3/TMS，ppm):
8.54(s，1H)；7.56(s，1H)；7.33(d，J＝7.8Hz，1H)；7.01(d，J＝7.8Hz，1H)；6.43(s，1H)；3.68(m，1H)；3.50～3.59(t，J＝6.3Hz，4H)；1.73～2.06(t，J＝6.3Hz，4H)；1.99～2.35(d，J＝7.8Hz，2H)；1.64(m，1H)；2.44～2.70(t，J＝6.3Hz，2H)；1.36(t，J＝6.3Hz，2H)；1.70(m，1H)；0.93(s，6H)。
MS：m/z(M+H+)479.3。
Comparative example Compounds I5Synthesis of (2)
Figure BDA0002544471340000113
With reference to example 1, wherein step 4 replaces the product of step 1 with cyclohexanecarboxylic acid, Compound I is conveniently prepared52.4g, HPLC content 98.3%, LC-MS: 416.7.
example 5 solubility test
The solubility is measured according to the method of the national pharmacopoeia 2015 edition at the room temperature of 23 ℃.
Figure BDA0002544471340000114
Figure BDA0002544471340000121
It can be seen that the water solubility of the present invention is increased by 8 times or more, and is pH-dependent.
Example 6 chemical stability test
The sample was placed in hot water at 80 ℃ for 6h and sampled for HPLC analysis:
item Parent Compound (%) Product of step 3 (%) Pregabalin (%)
Compound I1 98.6 0.7 0.7
Compound I2 99.1 0.4 0.4
Compound I3 99.3 0.3 0.3
Compound I4 98.6 0.2 0.2
Compound I5 97.2 1.4 ——
The experimental result shows that the compound aqueous solution is stable and remarkable.
Example 7 evaluation of analgesic Effect
ddY mice were grown under fasted conditions for at least 16h while allowing free water intake and were orally administered a solution or solvent (0.1ml/5g) of the test compound. As solvent for the test compound solution, dimethylsulfoxide: tween 80: 27% hydroxypropyl beta cyclodextrin (1:1: 8). A solution of 0.6% acetic acid (0.1ml/5g) was administered intraperitoneally 45min after administration to induce a writhing response (i.e., stretching or arching movements). The number of writhing reactions that occurred from 10min after the administration of the acetic acid solution to 10min thereafter was counted, and the number was designated as an index of pain. The number of reactions in the group to which the solvent was administered was designated as 100% and the concentration of test compound that inhibited 50% of such reactions was designated as the ED50 value, with the results given in the following table:
compound (I) ED50(mg/kg) [ 90% confidence interval]
Compound I1 0.12[0.09-0.20]
Compound I2 0.19[0.11-0.25]
Compound I3 0.16[0.13-0.27]
Compound I4 0.27[0.16-0.42]
Compound I5 8.67[6.57-10.23]
Pregabalin 2.42[1.62-3.95]
The test results show that the compounds of the present invention can provide excellent analgesic effects by oral administration.

Claims (10)

1. A dual soluble epoxyhydrolase and gamma-aminobutyric acid inhibitor represented by formula (I) and pharmaceutically acceptable salts thereof:
Figure FDA0002544471330000011
wherein:
R1selected from-H or-F or-Cl or-Br or-CN or-NO2；
R2Is selected from-CF3or-OCF3or-CN or-NO2。
2. The dual soluble epoxy hydrolase and gamma aminobutyric acid inhibitor according to claim 1, wherein said dual soluble epoxy hydrolase and gamma aminobutyric acid inhibitor is selected from the group consisting of: r1is-H or-F or-Cl, R2is-CF3or-OCF3。
3. The dual soluble epoxyhydrolase and gamma-aminobutyric acid inhibitor and the pharmaceutically acceptable salt thereof according to claims 1-2, wherein: the compound is preferably of the structure:
Figure FDA0002544471330000012
4. the dual soluble epoxy hydrolase and gamma-aminobutyric acid inhibitor as claimed in claims 1 to 3, wherein said dual soluble epoxy hydrolase and gamma-aminobutyric acid inhibitor comprises: the pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulfate, nitrate, phosphate, formate, acetate, propionate, oxalate, malonate, butyrate, lactate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, maleate, benzoate, succinate, picrate, tartaric acid, citrate or fumarate.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
6. An analgesic comprising a dual inhibitor of soluble epoxyhydrolase and gamma-aminobutyric acid according to any one of claims 1 to 5 and pharmaceutically acceptable salts thereof.
7. A therapeutic or prophylactic agent for neuropathic pain, comprising the soluble epoxyhydrolase and gamma-aminobutyric acid dual inhibitor according to any one of claims 1 to 5, and a pharmaceutically acceptable salt thereof.
8. A therapeutic or prophylactic agent for inflammatory pain comprising a dual inhibitor of soluble epoxyhydrolase and gamma-aminobutyric acid according to any one of claims 1 to 5, and pharmaceutically acceptable salts thereof.
9. Use of a dual inhibitor of soluble epoxyhydrolase and gamma-aminobutyric acid and pharmaceutically acceptable salts thereof according to any one of claims 1 to 5 for the manufacture of analgesics.
10. Use of a dual soluble epoxyhydrolase and gamma-aminobutyric acid inhibitor according to any one of claims 1 to 5, and pharmaceutically acceptable salts thereof, for the manufacture of a therapeutic or prophylactic agent for neuropathic pain.
CN202010556427.5A 2020-06-17 2020-06-17 Soluble epoxy hydrolase and gamma-aminobutyric acid dual inhibitor and application thereof Pending CN111574432A (en)

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CN102664631A (en) * 2012-04-18 2012-09-12 成都阜特科技有限公司 Current loop isolation, transmission and integration module and multi-channel current transmitting system thereof
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