CN102093320B - Soluble epoxide hydrolase inhibitor - Google Patents
Soluble epoxide hydrolase inhibitor Download PDFInfo
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- CN102093320B CN102093320B CN 200910200156 CN200910200156A CN102093320B CN 102093320 B CN102093320 B CN 102093320B CN 200910200156 CN200910200156 CN 200910200156 CN 200910200156 A CN200910200156 A CN 200910200156A CN 102093320 B CN102093320 B CN 102093320B
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- 108020002908 Epoxide hydrolase Proteins 0.000 title claims abstract description 39
- 102100025357 Lipid-phosphate phosphatase Human genes 0.000 title claims abstract description 39
- 229940122183 Epoxide hydrolase inhibitor Drugs 0.000 title abstract 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 49
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 28
- 239000000047 product Substances 0.000 claims description 26
- 239000012043 crude product Substances 0.000 claims description 23
- 238000010898 silica gel chromatography Methods 0.000 claims description 13
- RGTYVRBWCGZTIV-UHFFFAOYSA-N C1=CC=C(C=C1)C(=O)Cl=S(=O)=O Chemical compound C1=CC=C(C=C1)C(=O)Cl=S(=O)=O RGTYVRBWCGZTIV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 239000012264 purified product Substances 0.000 claims description 11
- 238000010025 steaming Methods 0.000 claims description 11
- 229940127514 Epoxide Hydrolase Inhibitors Drugs 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
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- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 15
- 230000036772 blood pressure Effects 0.000 abstract description 11
- 239000001257 hydrogen Substances 0.000 abstract description 5
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- 230000037005 anaesthesia Effects 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 208000010513 Stupor Diseases 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
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- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- JPQNWOYCDFRAPV-UHFFFAOYSA-N 1-methyldiazepine Chemical compound CN1C=CC=CC=N1 JPQNWOYCDFRAPV-UHFFFAOYSA-N 0.000 description 1
- XTNOEYFQXCQKLC-UHFFFAOYSA-N 18-(oxiren-2-yl)octadeca-15,17-dienoic acid Chemical compound C1=C(C=CC=CCCCCCCCCCCCCCC(=O)O)O1 XTNOEYFQXCQKLC-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N CN1CCOCC1 Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-O C[NH+]1CCNCC1 Chemical compound C[NH+]1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-O 0.000 description 1
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- 102000004190 Enzymes Human genes 0.000 description 1
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- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
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- PNFXYPVLWQULSM-UHFFFAOYSA-N O=C(c1cccc(S(=O)=O)c1)Nc(cc1)ccc1S(C(F)(F)F)(=O)=O Chemical compound O=C(c1cccc(S(=O)=O)c1)Nc(cc1)ccc1S(C(F)(F)F)(=O)=O PNFXYPVLWQULSM-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
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- 125000003275 alpha amino acid group Chemical group 0.000 description 1
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- 150000001412 amines Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a soluble epoxide hydrolase inhibitor, which has the following structural formula I, wherein R1 is N-R2R3; R2 and R3 are hydrogen, C1-C4 alkyl, aromatic ring, aromatic heterocyclic ring, or C1-C4 alkyl connected with the aromatic ring or the aromatic heterocyclic ring respectively; and the R2 can also be connected with the R3 to form a ring, then R1 is a quinary, hexahydric or heptabasic heterocyclic ring containing 1 nitrogen atom or 1 oxygen atom, and the nitrogen atom can be directly connected with the hydrogen and can also be connected with the C1-C4 alkyl. Rat experiment group results in an anesthesia state and a non-anesthesia state show that the inhibitor has certain blood pressure reducing effect, can be used for preparing medicaments for preventing and treating cardiovascular diseases, and has broad clinical application prospect. The invention provides a preparation method.
Description
Technical field
The present invention relates to pharmaceutical preparation, be specifically related to a kind of soluble epoxide hydrolase inhibitors.
Background technology
The M ﹠ M of cardiovascular disorder surpasses neoplastic disease and leaps to the first.Pharmacological agent is successfully to prevent and treat extremely important integral part in the cardiovascular disorder aggregate measures.More than the cardiovascular agent kind, the selling market is big, first of the Jun Ju world medicine.Yet existing Side effects of pharmaceutical drugs and untoward reaction day show outstanding, develop new medicine, particularly based on the original new drug safely and effectively of new role mechanism, are still the field of giving priority to of pharmacy industry.
Soluble epoxide hydrolase (sEH) extensively exists in mammalian tissues, plays an important role in the metabolism of lipid epoxy compounds in vivo, mainly is responsible for epoxy eicosatrienoic acid (epoxyeicosatrienoicacids, degraded EETs).EETs is that a class has powerful bioactive endogenous lipid epoxy compounds, as the main component of the hyperpolarization factor of endothelium derivation, have powerful cardiovascular effect and anti-inflammatory actions such as the ion running of adjusting and genetic expression, vasodilation, anti-inflammatory and short fibrinolytic.EETs transformation period in cell is shorter, and main is the more weak diol compound of corresponding biological activity through the rapid catalytic hydrolysis of sEH.Suppress the hydrolysis that sEH reduces EETs, thereby increase its concentration and cardiovascular regulatory function in cell, therefore the sEH inhibitor becomes alleviation and treats the painful potential means of multiple cardiovascular disorder and anti-inflammatory town such as hypertension, end-organ damage, myocardial hypertrophy.Relevant studies show that, EETs regulates blood pressure at blood vessel, kidney and heart level vasodilation.Provide further foundation for suppressing sEH treatment hypertension.Suppress the relevant end-organ damage of the cardiovascular disorder of sEH and have provide protection.The sEH inhibitor plays the effect of prevention and treatment myocardial hypertrophy by the activation of blocking-up nf kappaB, thereby effectively prevents the generation of the heart disorder that myocardial hypertrophy is relevant.Discovery and normal mouse comparisons such as Seubert; the utilization ratio of sEH gene knockout mice myocardial preservation EETs increases; myocardial function behind the ischemia/reperfusion injury improves, and the formation of myocardial infarction reduces, for sEH inhibitor for treating ischemia/reperfusion injury provides strong basis.In addition, discovering in several animal models, the sEH inhibitor has the painful effect in significant anti-inflammatory town, and drug combination can also increase the painful effect in town of nonsteroidal anti-inflammatory drug.Current research shows that EETs also has important non-cardiovascular function, has the effect of regulating the fat and sugar metabolism, increases Regular Insulin sensitivity, thereby the sEH inhibitor also becomes the focus of paying close attention in the metabolic disease field such as diabetes.
SEH inhibitor and existing cardiovascular agent relatively have its unique advantage: 1) compound is by suppressing the metabolism lytic enzyme, and the concentration that increases endogenous biologically active substance EETs reaches therapeutic action, directly do not disturb person's physiological processes, thereby toxic side effect is less; 2) biological action of EETs is extensive, can prevent simultaneously and treats multiple cardiovascular relevant symptom, is not a certain treatment index of single improvement, thereby can reduces the M ﹠ M of diseases related comprehensively; 3) inhibitor of sEH safely and effectively newly developed also can be applicable to rheumatic arthritis, the treatment of other major diseases such as diabetes.World's pharmacy giants such as Pfizer, Novartis and German Boehringer Ingelheim release a series of patent compounds in the recent period, but mostly also in the preclinical study stage.Have only the treatment hypertension of the Arete of u s company exploitation and the small molecules sEH inhibitor AR9281 of diabetes to enter phase ii clinical trial at present, in case succeed in developing, expection will become a cookle medicine.The alkyl urea compounds that present existing small molecules sEH inhibitor is 1,3 replacement mostly.The external inhibition activity to sEH of this compounds is higher, and half inhibiting rate can reach the nmole scope, also shows significant curative effect on animal model.Yet the physical properties of ureas functional group inherence determines the poorly water-soluble of this compounds, and bioavailability is low, has greatly limited it and has become the property of medicine and clinical application.Seeking non-ureas molecule has become the main direction of Development of New Generation sEH inhibitor.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, seeks new non-ureas molecular skeleton, develops into the high more excellent sEH inhibitor of the property of medicine.
The present invention is target spot with sEH, use international original new drug research mode " screening of the optimization of the discovery-lead compound of high flux screening-lead compound-clinical candidate compound ", find good water solubility, low toxicity and active high becomes the property of medicine to be better than the sEH inhibitor of existing compound.
The invention provides a kind of soluble epoxide hydrolase inhibitors.
Compound of the present invention has following structural I:
Wherein, R
1Can be N-R
2R
3, R
2And R
3Be respectively hydrogen, C
1-C
4Alkyl, aromatic nucleus, aromatic heterocycle or the C that connects with aromatic nucleus or aromatic heterocycle
1-C
4Alkyl;
R
2Can and R
3Connect into ring, at this moment, R
1For containing five yuan, hexa-atomic or seven membered heterocyclic of 1～2 nitrogen-atoms and/or 1 Sauerstoffatom, nitrogen-atoms can directly be connected with hydrogen, also can with C
1-C
4Alkyl connect.
Compound formula I of the present invention comprises its steric isomer, hydrate or pharmacy acceptable salt, wherein R
1Be N-methylamino ethyl, 3-furyl, 4-pyridyl or 4-picolyl.
Table 1 The compounds of this invention
The present invention is skeleton with fragrant phenyl ring, and sulphonamide and two substituting groups of benzamide are arranged, its structure of modification respectively at its 1,3: the morpholine structure in the sulphonamide can be by other oxazas, nitrogen nitrogen heterocyclic, and substituting groups such as other secondary fat amidos replace.Its synthetic route is short, and synthesis technique is simple, reaction conditions gentleness, reaction yield height.Phenylamino in the benzamide can with a series of amino comprise replacement fragrant ammonia, fatty amine etc. substitute.NH in bibliographical information urea or the acid amides is the pharmacophoric group of reusing, it with sEH in the residual base of relevant amino acid form hydrogen bond, influence the avidity of compound and enzyme.Therefore, structure of modification of the present invention is mainly selected the primary amine of replacement for use, to guarantee a keeping hydrogen atom on the nitrogen in the acid amides.
Another object of the present invention has provided the preparation method of above-mentioned soluble epoxide hydrolase inhibitors.
The preparation method of this inhibitor comprises the following steps:
(1) 3-chlorine sulfonyl-benzoyl chlorine is added in the dry methylene dichloride, ice bath stirs, and adds triethylamine and 4-trifluoromethyl sulfonanilide more successively, and stirred overnight at room temperature gets crude product;
Wherein, when 3-chlorine sulfonyl-benzoyl chlorine was 11mmol, the dry methylene chloride of adding was 10～20mL, is preferably 15mL;
The temperature of ice bath is-20～0 ℃, is preferably-10 ℃;
When 3-chlorine sulfonyl-benzoyl chlorine was 11mmol, the amount of the triethylamine that adds was 1～1.2 times of equivalent, preferred 1.1 times of equivalents; Be 1.2mmol;
When 3-chlorine sulfonyl-benzoyl chlorine was 11mmol, the equivalent of required 4-trifluoromethyl sulfonanilide was 0.8～1.0 times of equivalent, and namely 0.9～1.1mmol is preferably 0.9 times of equivalent, i.e. 1.0mmol.
(2) get step reaction gained crude product, join methylene dichloride, add triethylamine more successively, aminated compounds, room temperature continues reaction, revolves the steaming desolventizing; Described aminated compounds is morpholine, 2-methoxy ethyl ammonia, N
1-methylethyl-1,2-diamines, piperazine, N methyl piperazine, 1-methyl diazepine, the amino furans of 3-, 4-aminopyridine, 3-furans amino, 4-pyridine amino or pyridine 4-methylamino;
Wherein, when getting previous step reaction gained crude product was 2mL, the methylene dichloride of required adding was 8～15mL, is preferably 10mL;
When get step reaction gained crude product was 2mL, the triethylamine of required adding was 1.0～1.5mmol, is preferably 1.3mmol;
When getting previous step reaction gained crude product was 2mL, the aminated compounds of required adding was 0.8～1.2mmol, is preferably 1.0mmol; It is 1～5h that room temperature continues the reaction times, is preferably 3h;
(3) get the step desolventizing and obtain the product purification by silica gel column chromatography, obtain purified product.
The eluent PE (sherwood oil) of purification by silica gel column chromatography product and EA (ethyl acetate), the proportioning of PE and EA is 3: 1v/v.
Another purpose of the present invention has provided above-mentioned soluble epoxide hydrolase inhibitors in preparation prevention and the application for the treatment of in the cardiovascular disease medicine.
Medicine of the present invention is to contain the pharmaceutical composition that compound of Formula I and steric isomer, hydrate or pharmacy acceptable salt and pharmaceutically acceptable carrier are made.
The present invention has detected the inhibition activity of following compounds to sEH:
Table 2 part of compounds is to the inhibition activity of sEH
The display part compound is to the inhibition IC of sEH as a result
50Be nM level (table 2), prove the inhibitor that this series compound is sEH; According to the physiological action of sEH, can infer that these compounds can be used for treating cardiovascular disorder, kidney and heart level vasodilation are regulated blood pressure, and the end-organ damage relevant to cardiovascular disorder has provide protection.In prevention and treatment cardiovascular disorder, especially treat the hypertension aspect and have broad application prospects.
Through preliminary quasi-medicated property research, the inventor chooses compound 1a (table 1) and further studies its hypotensive effect.The pharmacological results is as follows:
1, safety testing
Get 20 of the mouse of body weight 20 ± 2g, male and female half and half are pressed 0.8mg/20g and are irritated stomach compound 1, (concentration is the suspension of 25mg/ml), observe the death condition of animal in 14 days continuously, the result is in 14 days, all animal feed activities are normal, do not have death, assert the LD of its oral administration of compound
50＞5g/mg belongs to actual nontoxic.
2, acute step-down result:
Observe compound respectively to the hypotensive effect of anesthesia with the non-narcotization rat.
2.1, to the acute hypotensive effect of non-narcotization rat
Get 45 of healthy wistar rats, the male and female dual-purpose, body weight is 180～220g, divides three groups at random, 15 every group.First group: abdominal injection is given birth to salt solution; Second group: the abdominal injection test compounds; The 3rd group: abdominal injection positive control compound (pannonit).Dosage is 500 μ g/kg, and investigational agent all is made into the solution of 1mg/1ml).The mouse caudal artery blood pressure instrument of respectively three groups of rats being packed into is treated administration behind its blood pressure stabilization, measures blood pressure and heart rate after 60 minutes.The results are shown in Table 3:
The acute step-down result of the non-narcotization rat of table 3 compound 1a (500 μ g/kg)
2.2, to the acute hypotensive effect of narcosis rat
Get 70 of healthy wistar rats, male and female half and half, body weight are 180～220g, divide three groups at random, control group administered physiological saline 10), all the other two groups are all adopted (500 μ g/kg, 800 μ g/kg, 1000 μ g/kg) three dosage groups (reagent all is made into the solution of 1mg/1ml).Respectively three groups of rats are pressed 0.6ml/100g anesthesia with 25% urethane, face upward the position and fix, expose trachea T shape and cut, connect the animal respirator, separate carotid artery.Wash plastics tubing and be inserted into separation carotid artery with heparin, connect four road physiographs, recording blood pressure and heart rate, it is stand-by to separate femoral vein.After rat blood pressure and the heart rate stabilization, respectively by the administration of above-mentioned dosage femoral vein.60 minutes blood pressure and heart rate after the METHOD FOR CONTINUOUS DETERMINATION administration the results are shown in Table 4:
Rat acute step-down result under the narcosis of table 4 compound 1a
Annotate: heavy dose of group (1000 μ g/kg), middle dosage group (800 μ g/kg), small dose group (500 μ g/kg)
Rat experiment group result shows under the non-narcotization, behind the injection compound 1a 60 minutes, certain hypotensive effect is arranged, but heart rate seemingly has the trend of rising, because the equal waking state of rat, when blood pressure drops, the heart of normal function is because Starting regulates the compensatory quickening of heart rate.
Rat experiment group result shows under the narcosis, behind the injection compound 1a 2～35 minutes, certain hypotensive effect is arranged.Heart rate descends after the administration, and heavy dose of (1000 μ g/kg), heart rate descends can reach 24.4%.This point has Special Significance to cardiovascular system diseases.
Under the two states, blood pressure all descends behind the injection pannonit, and degree is bigger, but it is all seemingly on the rise than weak point and heart rate relatively to hold time.
Compared with the prior art the technology of the present invention has following advantage and effect:
1) compound 1a can be used for treating cardiovascular disorder, and kidney and heart level vasodilation are regulated blood pressure, and the end-organ damage relevant to cardiovascular disorder has provide protection.It is little to have toxic side effect, and biological action is extensive, drug safety advantages of higher and effect.In prevention and treatment cardiovascular disorder, especially treat the hypertension aspect and have broad application prospects.
2) compound is by suppressing the metabolism lytic enzyme, and the concentration that increases endogenous biologically active substance EETs reaches therapeutic action, directly do not disturb person's physiological processes, thereby toxic side effect is less;
3) biological action of EETs is extensive, can prevent simultaneously and treats multiple cardiovascular relevant symptom, is not a certain treatment index of single improvement, thereby can reduces the M ﹠ M of diseases related comprehensively.
Embodiment
Embodiment 1
Synthesizing of 3-(4-trifluoromethyl sulfonyl) phenyl amino formyl radical-1-SULPHURYL CHLORIDE
In the 250mL three-necked flask, with 3-chlorine sulfonyl-benzoyl chlorine (5.84g, 24.4mmol) add in the dry methylene dichloride (16.6mL),-10 ℃ of ice baths stir, add successively again triethylamine (3.4mL, 24.4mmol) and 4-trifluoromethyl sulfonanilide (5g, 22.2mmol), stirred overnight at room temperature gets crude product.
Embodiment 2
Synthesizing of 3-(morpholine base alkylsulfonyl)-N-(4-(trifluoromethyl sulfonyl) phenyl) benzamide (1a)
Get previous step reaction gained crude product 2mL, join methylene dichloride 10mL, add successively again triethylamine (0.5mL, 3.47mmol), morpholine (232mg, 2.67mmol), room temperature continues reaction 3h, revolves the steaming desolventizing, utilizes silica gel column chromatography (PE: EA=3: 1) purified product, obtain the 750mg white products, productive rate is 71%.Product purity: 98%,
1HNMR (ppm) 8.62-7.91 (m, 9H), 3.67 (t, 4H), 2.9 (t, 4H) .MS (M
++ 1) 479, ultimate analysis (%): calculated value C, 45.18; H, 3.58; F, 11.91; N, 5.85; O, 20.06; S, 13.40; Measured value C, 45.15; H, 3.54; F, 11.89; N, 5.87; O, 20.05; S, 13.41.
Embodiment 3
3-(N-(2-methoxy ethyl) amino-sulfonyl)-N-(4-trifluoromethyl sulfonyl) phenyl) benzamide (1b) is synthetic
Get previous step reaction gained crude product 2mL, join methylene dichloride 10mL, add successively again triethylamine (0.5mL, 3.47mmol), 2-methoxy ethyl amino (200mg, 2.67mmol), room temperature continues reaction 6h, revolves the steaming desolventizing, utilizes silica gel column chromatography (PE: EA=4: 1) purified product, obtain the yellow product of 800mg, productive rate is 77.3%.Product purity: 97.8%,
1HNMR (ppm) 8.51-7.31 (m, 9H), 2.4 (br, 1H), 3.3 (t, 2H) .3.6 (t, 2H) .3.2 (s, 3H) .MS (M
++ 1) 467, ultimate analysis (%): calculated value C, 43.77; H, 3.67; F, 12.22; N, 6.01; O, 20.58; S, 13.75; Measured value C, 43.78; H, 3.66; F, 12.26; N, 6.02; O, 20.55; S, 13.73.
Embodiment 4
3-(N-(2-methylamino) amino-sulfonyl)-N-(4-trifluoromethyl sulfonyl) phenyl) benzamide (1c) is synthetic
Get previous step reaction gained crude product 2mL, join methylene dichloride 10mL, add triethylamine (0.5mL more successively, 3.47mmol), N, N-Boc-methyl ethylenediamine (466mg, 2.67mmol), room temperature continues reaction 5h, revolves the steaming desolventizing, utilize silica gel column chromatography (PE: EA=2: 1) purified product, obtain the yellow product of 760mg, this product is dissolved in methylene dichloride 4mL, drip trifluoracetic acid (1mL, 13.5mmol), the stirring at room reaction is spent the night.Concentrate, add saturated NaHCO
3Solution is crossed filter solid, the washing both sides, and drying obtains the 600mg white solid, and productive rate is 58.1%.Product purity: 97.8%,
1HNMR (ppm) 8.55-7.21 (m, 9H), 2.1 (br, 2H), 3.3 (t, 2H) .2.9 (t, 2H) .2.5 (s, 3H).MS (M
++ 1) 466, ultimate analysis (%): calculated value C, 43.87; H, 3.90; F, 12.24; N, 9.03; O, 17.19; S, 13.78; Measured value C, 43.89; H, 3.88; F, 12.26; N, 9.01; O, 17.22; S, 13.74.
Embodiment 5
3-(piperazinyl alkylsulfonyl)-N-(4-trifluoromethyl sulfonyl) phenyl) the synthetic previous step reaction gained crude product 2mL that gets of benzamide (1d); join methylene dichloride 10mL; add triethylamine (0.5mL more successively; 3.47mmol); N-Boc-piperazine (497mg; 2.67mmol); room temperature continues reaction 6h; revolve the steaming desolventizing, (PE: EA=4: 1) purified product obtains the yellow product of 960mg to utilize silica gel column chromatography; this product is dissolved in methylene dichloride 4mL; (1mL, 13.5mmol), the stirring at room reaction is spent the night to drip trifluoracetic acid.Concentrate, add saturated NaHCO
3Solution is crossed filter solid, the washing both sides, and drying obtains the 780mg white solid, and productive rate is 73.7%.Product purity: 97.8%,
1HNMR (ppm) 8.21-7.11 (m, 9H), 3.2 (t, 4H) .3.7 (t, 4H) .2.5 (s, 1H).MS (M
++ 1) 478, ultimate analysis (%): calculated value C, 45.28; H, 3.80; F, 11.94; N, 8.80; O, 16.75; S, 13.43; Measured value C, 45.25; H, 3.83; F, 11.84; N, 8.90; O, 16.77; S, 13.41.
Embodiment 6
3-(N methyl piperazine base alkylsulfonyl)-N-(4-trifluoromethyl sulfonyl) phenyl) the synthetic previous step reaction gained crude product 2mL that gets of benzamide (1e); join methylene dichloride 10mL; add successively again triethylamine (0.5mL, 3.47mmol), 1-methylpiperazine (267mg; 2.67mmol); room temperature continues reaction 6h, revolves the steaming desolventizing, utilizes silica gel column chromatography (PE: EA=4: 1) purified product; obtain the yellow product of 850mg, productive rate is 77.8%.Product purity: 97.8%,
1HNMR (ppm) 8.70-6.54 (m, 9H), 3.1 (t, 4H) .3.8 (t, 4H) .2.3 (s, 3H).MS (M
++ 1) 492, ultimate analysis (%): calculated value C, 46.43; H, 4.10; F, 11.60; N, 8.55; O, 16.28; S, 13.05; Measured value C, 46.46; H, 4.07; F, 11.62; N, 8.53; O, 16.26; S, 13.07.
Embodiment 7
3-(diazepine base alkylsulfonyl)-N-(4-trifluoromethyl sulfonyl) phenyl) benzamide (1f) is synthetic
Get previous step reaction gained crude product 2mL, join methylene dichloride 10mL, add triethylamine (0.5mL more successively, 3.47mmol), the 1-Boc-4-diazepine (534mg, 2.67mmol), room temperature continues reaction 5h, revolve the steaming desolventizing, (PE: EA=4: 1) purified product obtains the yellow product of 687mg to utilize silica gel column chromatography, this product is dissolved in methylene dichloride 4mL, (1mL, 13.5mmol), the stirring at room reaction is spent the night to drip trifluoracetic acid.Concentrate, add saturated NaHCO
3Solution is crossed filter solid, the washing both sides, and drying obtains the yellow product of 630mg, and productive rate is 57.7%.Product purity: 97.8%,
1HNMR (ppm) 8.21-7.02 (m, 9H), 3.1 (m, 2H) .1.5 (m, 2H) .2.4 (m, 2H) .2.7 (m, 2H) .3.3 (m, 2H) .2.4 (s, 1H).MS (M
++ 1) 492, ultimate analysis (%): calculated value C, 46.43; H, 4.10; F, 11.60; N, 8.55; O, 16.28; S, 13.05; Measured value C, 46.41; H, 4.13; F, 11.57; N, 8.58; O, 16.29; S, 13.04.
Embodiment 8
3-(furans amino-sulfonyl)-N-(4-trifluoromethyl sulfonyl) phenyl) benzamide (1g) is synthetic
Get previous step reaction gained crude product 2mL, join methylene dichloride 10mL, add successively again triethylamine (0.5mL, 3.47mmol), the amino furans (221.6mg of 3-, 2.67mmol), room temperature continues reaction 6h, revolves the steaming desolventizing, utilizes silica gel column chromatography (PE: EA=4: 1) purified product, obtain the yellow product of 710mg, productive rate is 67.3%.Product purity: 97.8%,
1HNMR (ppm) 8.46-7.36 (m, 9H), 3.0 (br, 1H), 6.5 (s, 1H) .7.5 (d, 1H) .6.2 (d, 1H).MS (M
++ 1) 475, ultimate analysis (%): calculated value C, 45.57; H, 2.76; F, 12.01; N, 5.90; O, 20.23; S, 13.52; Measured value C, 45.54; H, 2.78; F, 12.04; N, 5.87; O, 20.26; S, 13.50.
Embodiment 9
3-(pyridine amino-sulfonyl)-N-(4-trifluoromethyl sulfonyl) phenyl) benzamide (1h) is synthetic
Get previous step reaction gained crude product 2mL, join methylene dichloride 10mL, add successively again triethylamine (0.5mL, 3.47mmol), 4-aminopyridine (251mg, 2.67mmol), room temperature continues reaction 6h, revolves the steaming desolventizing, utilizes silica gel column chromatography (PE: EA=4: 1) purified product, obtain the yellow product of 690mg, productive rate is 64.1%.Product purity: 97.8%,
1HNMR (ppm) 8.68-7.16 (m, 9H), 4.0 (br, 1H), 6.7 (d, 2H) .8.5 (d, 2H).MS (M
++ 1) 486, ultimate analysis (%): calculated value C, 47.01; H, 2.91; F, 11.74; N, 8.66; O, 16.48; S, 13.21; Measured value C, 47.03; H, 2.87; F, 11.71; N, 8.69; O, 16.44; S, 13.25.
Embodiment 10
3-(N-4-methylamino pyridyl sulfonyl)-N-(4-trifluoromethyl sulfonyl) phenyl) benzamide (1i) is synthetic
Get previous step reaction gained crude product 2mL, join methylene dichloride 10mL, add successively again triethylamine (0.5mL, 3.47mmol), 4-methylamino pyridine (288mg, 2.67mmol), room temperature continues reaction 6h, revolves the steaming desolventizing, utilizes silica gel column chromatography (PE: EA=4: 1) purified product, obtain the yellow product of 680mg, productive rate is 61.3%.Product purity: 97.8%,
1HNMR (ppm) 8.81-7.25 (m, 9H), 4.0 (br, 1H), 6.6 (d, 2H) .8.4 (d, 2H) .4.3 (s, 2H).MS (M
++ 1) 500, ultimate analysis (%): calculated value C, 48.09; H, 3.23; F, 11.41; N, 8.41; O, 16.02; S, 12.84; Measured value C, 48.05; H, 3.28; F, 11.40; N, 8.42; O, 16.12; S, 12.74.
Claims (10)
1. soluble epoxide hydrolase inhibitors is characterized in that described soluble epoxide hydrolase inhibitors has following structural I:
Wherein, R
1For;
Or
2. the preparation method of soluble epoxide hydrolase inhibitors according to claim 1 is characterized in that this method comprises the following steps:
R wherein
1Definition according to claim 1;
(1) 3-chlorine sulfonyl-benzoyl chlorine is added in the dry methylene dichloride, ice bath stirs, and adds triethylamine and 4-trifluoromethyl sulfonanilide more successively, and stirred overnight at room temperature gets crude product;
Wherein, 3-chlorine sulfonyl-benzoyl chlorine is 11mmol, and the dry methylene chloride of adding is 10～20mL;
(2) get step reaction gained crude product, join methylene dichloride, add triethylamine, aminated compounds R more successively
1H, room temperature continues reaction, revolves the steaming desolventizing;
(3) get the step desolventizing and obtain the product purification by silica gel column chromatography, obtain purified product.
3. according to the method for claim 2, it is characterized in that step (1) is described when 3-chlorine sulfonyl-benzoyl chlorine is 11mmol, the dry methylene chloride of adding is 15mL.
4. according to the method for claim 2, it is characterized in that the temperature of step (1) ice bath is-20～0 ℃; When 3-chlorine sulfonyl-benzoyl chlorine was 11mmol, the amount of the triethylamine that adds was 1～1.2 times of equivalent; When 3-chlorine sulfonyl-benzoyl chlorine was 11mmol, the equivalent of required 4-trifluoromethyl sulfonanilide was 0.8～1.0 times of equivalent.
5. according to the method for claim 4, it is characterized in that the temperature of step (1) ice bath is-10 ℃; When 3-chlorine sulfonyl-benzoyl chlorine was 11mmol, the amount of the triethylamine that adds was 1.1 times of equivalents; When 3-chlorine sulfonyl-benzoyl chlorine was 11mmol, the equivalent of required 4-trifluoromethyl sulfonanilide was 0.9 times of equivalent.
6. according to the method for claim 2, it is characterized in that in the step (2) that when get step reaction gained crude product was 2mL, the methylene dichloride of required adding was 8～15mL; When get step reaction gained crude product was 2mL, the triethylamine of required adding was 1.0～1.5mmol; When getting previous step reaction gained crude product is 2mL, the aminated compounds R of required adding
1H is 0.8～1.2mmol; It is 1～5h that room temperature continues the reaction times.
7. according to the method for claim 6, it is characterized in that in the step (2) that when get step reaction gained crude product was 2mL, the methylene dichloride of required adding was 10mL; When get step reaction gained crude product was 2mL, the triethylamine of required adding was 1.3mmol; When getting previous step reaction gained crude product is 2mL, the aminated compounds R of required adding
1H is 1.0mmol, and it is 3h that room temperature continues the reaction times.
8. according to the method for claim 2, it is characterized in that the eluent of step (3) purification by silica gel column chromatography product is PE and EA, the proportioning of PE and EA is 3: 1v/v.
9. the application of soluble epoxide hydrolase inhibitors in preparation prevention and treatment cardiovascular disease medicine according to claim 1.
10. according to the application of claim 9, it is characterized in that described medicine is to contain the pharmaceutical composition that claim 1 soluble epoxide hydrolase inhibitors and pharmacy acceptable salt and pharmaceutically acceptable carrier thereof are made.
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| SG10201608528YA (en) | 2011-12-21 | 2016-12-29 | Novira Therapeutics Inc | Hepatitis b antiviral agents |
| WO2013112751A1 (en) * | 2012-01-25 | 2013-08-01 | The Trustees Of Columbia University In The City Of New York | Potent non-urea inhibitors of soluble epoxide hydrolase |
| JP2015533782A (en) | 2012-08-28 | 2015-11-26 | ヤンセン・サイエンシズ・アイルランド・ユーシー | Sulfamoyl-arylamide and its use as a medicament for the treatment of hepatitis B |
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| CA2932551A1 (en) | 2014-02-06 | 2015-08-13 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
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