CN108409727A - A kind of inhibitors of fatty amide hydrolase and preparation method thereof - Google Patents
A kind of inhibitors of fatty amide hydrolase and preparation method thereof Download PDFInfo
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a kind of inhibitors of fatty amide hydrolase and preparation method thereof, structural formula isWherein, X is selected from C；R1Selected from H；R2Selected from H；R3Selected from H.Compound by test has inhibitory activity well, hFAAH IC for people and rat fat hydroamidase50（nM）For 28, rFAAH IC50（nM）It is 110.Illustrate the follow-up research and development that the compound of the present invention can be as inhibitors of fatty amide hydrolase for the preparation of related drugs.
Description
It is on October 25th, 2017 that the application, which is the applying date, entitled " a kind of application No. is 2017110102607
The divisional application of the patent of inhibitors of fatty amide hydrolase and preparation method thereof ".
Technical field
The present invention relates to a kind of inhibitors of fatty amide hydrolase and preparation method thereof, belong to pharmaceutical chemistry, Pharmaceutical Analysis,
The combination in the fields such as pharmaceutical preparation and pharmaceutical activity test.
Background technology
Fatty amide hydrolase（Fatty acid amide hydrolase, FAAH）It is a kind of inner membrance amide FAAH signals
Family protein enzyme, it is many biologically active fatty acid amides in organism（Fatty acid amide）Messenger molecule
Major catalytic hydrolyzes metabolic enzyme.The fatty amide hydrolase being originally found is found in liver by Schmid and his colleagues
N- acyl ethanol amines amidohydrolase.This hydrolase can be by N- acyl ethanol amines（NAE）Hydrolysis generate aliphatic acid and
Ethanol amine.1996, Cravatt etc. came out this enzyme clone, is named as fatty amide hydrolase（FAAH）.In human body
Fatty amide hydrolase enzyme contains 597 amino acid, molecular weight 63KDa.Fatty amide hydrolase is mainly distributed on microsome
And on the film of mitochondria.FAAH is appeared in Various Tissues, including head, intestines, liver, testis, uterus, kidney, eyes, spleen and lung etc..
In the brain, FAAH is also different in not same district expression degree, most strong in globus pallidus region and hippocampus activity, and in brains
Activity is worst；In immune system, FAAH activity is by lymphocyte and Expression of Macrophages.FAAH is as endocannabinoids system
The forming member of system plays an important role to the termination of cannboid signal, be the nervous system disease, inflammation, metabolic disease and
The potential target spot for the treatment of cardiovascular disease.
The catalytic center of FAAH is the catalytic triads that Ser241, Ser217 and Lysl42 are constituted, and contains multiple channels
And chamber, including film access channel（Membrane access channel, MAC）, by active site and electrodes method film surface phase
Even；Cytoplasm accesses channel, and hydroaropic substance is allowed to exit activated centre（cytosolic access channel）；In conjunction with fat
The hydrophobic region of fat acid chain is known as fatty acid chain combined area（Acyl chain-binding pocket, ABP）, eutectic is adjusted
The fatty acid chain of body inhibitor.
Although not there is the listing of FAAH inhibitor also at present, has multiple drugs and surveyed in clinical and preclinical bioactivity
The examination stage.According to Thomson Reuters Cortellis statistics of database, there are multiple drugs to be in conceptual phase at present.
Invention content
One of the objects of the present invention is to provide a kind of inhibitors of fatty amide hydrolase, structural formula is
Wherein, X is selected from C or N；R1Selected from H or C；R2Selected from H, C or F；R3Selected from H, C, F or CH2CH3。
Further, salt or its solvated compounds.
Another object of the present invention is to provide a kind of synthetic routes of inhibitors of fatty amide hydrolase：
。
Another object of the present invention is to provide a kind of inhibitors of fatty amide hydrolase for treating, preventing or assisting to control
Treat the application in adjusting fatty amide hydrolase relevant disease in mammal and people, the disease such as pain, including it is acute
And it is chronic, the pain as caused by postoperative pain, chronic pain, pain caused by cancer, cancer chemotherapy, neuralgia, nociception pain, inflammatory
Bitterly, backache, the pain caused by the disease such as following various sources：Diabetic neuropathy including human immunodeficiency virus
Thermophilic nervous system type viral disease, pain such as post herpetic neuralgia caused by herpes zoster；Polyneuropathy, neurotoxicity, machinery
Neurotrosis, complication of wrist, amynologic mechanism such as multiple sclerosis.
Further, application of the inhibitors of fatty amide hydrolase in the drug for the treatment of pain.
Another object of the present invention is to a kind of compositions, including fatty amide hydrolase described in claim 1 to inhibit
Agent and pharmaceutically acceptable auxiliary material.
Further, the inhibitors of fatty amide hydrolase described in the composition is as sole active agent.
Obviously, the above according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Specific implementation mode
Intermediate one：The synthesis of the bromo- 1H- pyrroles -2- formyl chlorides of 4-
The bromo- 1H- pyrroles -2- formamides of compound 4- (10 mmol) are dissolved in 30 milliliters of dichloromethane, 5 milliliters are added thereto
Then DMF is added dropwise 3 grams of thionyl chlorides, is heated to flowing back, stir 5 hours, and decompression steams solvent, and 20 milliliters of first are added thereto
Benzene, decompression steam toluene and simultaneously take away remaining thionyl chloride, and products obtained therefrom is directly used in react in next step.1H-NMR
(400 MHz, CDCl3) δ: 7.17-7.22(m, 2H), 8.97(s, 1H)。
Intermediate two：The synthesis of the bromo- N- of 4- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -1H- pyrroles's -2- formamides
The bromo- 1H- pyrroles -2- acyl chlorides of the crude product 4- of previous step is dissolved in 40 milliliters of dichloromethane solutions, 10 millis are added thereto
Triethylamine is risen, control temperature is less than 10 DEG C, is added dropwise to 3- methyl-1s into system, and the two of 2,4- thiadiazoles -5- amine (12 mmol)
Chloromethanes solution, restore room temperature after being added dropwise, then stirring at normal temperature 10 hours is washed with 50 milliliter 5% of aqueous sodium carbonate
Wash reaction system, organic phase anhydrous Na2SO4Dry, after solvent evaporated, obtained solid flash column chromatography separation obtains 2.45
G light yellow solids, two step gross production rates 85%.1H-NMR (400 MHz, CDCl3) δ: 2.18(s, 3H), 6.78(d, 1H),
7.16(d, 1H), 8.83(s, 1H)。
Embodiment 1：The synthesis of N- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- phenoxy group -1H- pyrrole radicals -2- formamides
The bromo- N- of 4- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -1H- pyrroles -2- formamides (10 mmol) are dissolved in 30 ml toluene
In, copper sulfide (1 mmol) and cesium carbonate (12 mmol) are added thereto, stirs half an hour, phenol (12 is added thereto
Mmol), reacted 10 hours after system is heated to 100 DEG C.Then it is cooled to room temperature, is filtered, solvent evaporated, flash column chromatography point
From it is solid that 2.3 g off-white colors N- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- phenoxy group -1H- pyrrole radicals -2- formamides can be obtained
Body, yield 77%.1H-NMR (400 MHz, CDCl3) δ: 2.18(s, 3H), 6.23(d, 1H), 6.45(d,1H),
6.91-7.02(m, 3H), 7.29(m, 2H), 8.64(s, 1H).13C-NMR (75 MHz, CDCl3) δ:17.71,
108.26, 119.9, 120.66, 121.66, 124.89, 129.81, 143.43, 153.96, 162.46,
167.63, 173.89.LC-MS(ESI, pos, ion) m/z: 301[M+1]。
Embodiment 2：N- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- (2- pyridines oxygroup) -1H- pyrrole radicals -2- formamides
Synthesis
The bromo- N- of 4- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -1H- pyrroles -2- formamides (10 mmol) are dissolved in 30 ml toluene
In, copper sulfide (1 mmol) and cesium carbonate (12 mmol) are added thereto, stirs half an hour, 2 hydroxy pyrimidine is added thereto
(12 mmol), system are reacted 10 hours after being heated to 100 DEG C.Then it is cooled to room temperature, is filtered, solvent evaporated, flash column chromatography
Separation, can obtain the faint yellow N- of 2.4 g (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- (2- pyridines oxygroup) -1H- pyrrole radicals -2- first
Amide solid, yield 80%.1H-NMR (400 MHz, CDCl3) δ: 2.15(s, 3H), 6.00(d, 1H), 6.36-
6.38(m, 2H), 6.54(dd, 1H), 7.21(dd, 1H), 7.58(dt, 1H), 8.59(s, 1H).13C-NMR (75
MHz, CDCl3) δ: 17.71, 108.26, 116.02, 118.61, 120.82, 121.66, 137.45, 143.09,
148.62, 162.36, 162.46, 167.63, 173.89.LC-MS(ESI, pos, ion) m/z: 302[M+1]。
Embodiment 3：N- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- (3- fluorophenoxies) -1H- pyrrole radicals -2- formamides
Synthesis
The bromo- N- of 4- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -1H- pyrroles -2- formamides (10 mmol) are dissolved in 30 ml toluene
In, copper sulfide (1 mmol) and cesium carbonate (12 mmol) are added thereto, stirs half an hour, 3- fluorophenols (12 are added thereto
Mmol), reacted 10 hours after system is heated to 100 DEG C.Then it is cooled to room temperature, is filtered, solvent evaporated, flash column chromatography point
From the faint yellow N- of 2.6 g (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- (3- fluorophenoxies) -1H- pyrrole radicals -2- formyls can be obtained
Amine solid, yield 84%.1H-NMR (400 MHz, CDCl3) δ: 2.19(s, 3H), 6.07(d, 1H), 6.44(d,
1H), 6.68(m, 1H), 7.27(m, 1H), 7.46(m, 1H), 7.60(m, 1H), 8.85(s, 1H).13C-NMR
(75 MHz, CDCl3) δ: 17.71, 108.26, 108.49, 111.04, 116.13, 120.66, 121.66,
131.17, 143.43, 155.32, 162.46, 163.83, 167.63, 173.89.LC-MS(ESI, pos, ion)
m/z:319[M+1]。
Embodiment 4：N- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- (to ethyl phenoxy group) -1H- pyrrole radicals -2- formyls
The synthesis of amine
The bromo- N- of 4- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -1H- pyrroles -2- formamides (10 mmol) are dissolved in 30 ml toluene
In, copper sulfide (1 mmol) and cesium carbonate (12 mmol) are added thereto, stirs half an hour, paraethyl phenol is added thereto
(12 mmol), system are reacted 10 hours after being heated to 100 DEG C.Then it is cooled to room temperature, is filtered, solvent evaporated, flash column chromatography
Separation, can obtain 2.8 g N- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- (to ethyl phenoxy group) -1H- pyrrole radicals -2- formyls
Amine solid, yield 85%.1H-NMR (400 MHz, CDCl3) δ: 1.18(t, 3H), 2.18(s, 3H), 2.72(q.
2H). 6.07(d, 1H), 6.41(d, 1H), 7.01(m, 2H), 7.14(m, 2H), 8.62(s, 1H).13C-NMR
(75 MHz, CDCl3) δ: 13.19, 17.71, 27.82, 108.26, 120.66, 120.82, 121.66,
127.78, 139.92, 143.43, 152.41, 162.46, 167.63, 173.89.LC-MS(ESI, pos, ion)
m/z: 329[M+1]。
Embodiment 5：N- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- (2,3 dimethyl phenoxy) -1H- pyrrole radicals -2-
The synthesis of formamide
The bromo- N- of 4- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -1H- pyrroles -2- formamides (10 mmol) are dissolved in 30 ml toluene
In, copper sulfide (1 mmol) and cesium carbonate (12 mmol) are added thereto, stirs half an hour, paraethyl phenol is added thereto
(12 mmol), system are reacted 10 hours after being heated to 100 DEG C.Then it is cooled to room temperature, is filtered, solvent evaporated, flash column chromatography
Separation, can obtain 2.7 g yellow N- (3- methyl-1s, 2,4- thiadiazolyl groups -5) -4- (2,3 dimethyl phenoxy) -1H- pyrrole radicals -
2- formamide solids, yield 82%.1H-NMR (400 MHz, CDCl3) δ: 2.08(s, 3H), 2.18(s, 3H), 2.29
(s, 3H), 6.08(d, 1H), 6.35(d, 1H), 6.79-6.89(m, 3H), 8.68(s, 1H). 13C-NMR (75
MHz, CDCl3) δ: 13.38, 17.71, 19.79, 108.26, 117.32, 119.41, 121.66, 125.25,
125.31, 127.98, 137.11, 143.35, 154.08, 162.46, 167.63, 173.89.LC-MS(ESI,
pos, ion) m/z: 329[M+1]。
Test example 1：People and rat fat amide hydrolysis enzyme inhibition activity
The compounds of this invention is to people and rat fat hydroamidase（FAAH）Inhibitory activity, test method are same
CN103958473B, unless otherwise stated, all reagents are purchased from Sigma.It is summarized as follows：
Material and reagent：
People for analysis and rat fat hydroamidase（FAAH）Gene is by Patricelli etc.
（Biochemistry.1998,37（43）, 15177-87）Description.The fatty amide hydrolase that membrane-spanning domain is deleted（FAAH）Gene
It is cloned into pET15b（Novagen, #69661）（People FAAH）/pET28a（Novagen, #69864-3）（Rat FAAH genes）Matter
In grain and in Escherichia coli（Ecoli）It is expressed in BL21DE3.PGR07 plasmids（Takara Bio Inc, Japan）In companion's egg
White groEL-groES and fatty amide hydrolase（FAAH）Coexpression, so as to improve expression in escherichia coli protein it is molten
Xie Du.Such as Mileni（Proc NatlAcad Sci USA.2008,105（35）, 12820-4）In it is recorded, to express simultaneously
Enrichment protein.In short, using arabinose at room temperature（2mM）With isopropyl ss-D-1- thiogalactosides（IPTG）（1mM）
Induce LB culture mediums（Luria Broth）（2L）In bacterial cultures 20h.Culture is centrifuged into 10min at 1200 × g,
And by cell mass（cell pellet）It is resuspended in 100mL NaPi containing 20mM（pH7.4）, 100mM NaCl, nuclease（500u）、
Aprotinin（1μg/mL）And leupeptin（1μg/mL）Buffer solution in.Pass through sonic method（Amp 20%, pulse 15s × 15, ice
On）Lytic cell, and remove cell fragment by centrifuging 20min under 5000 × g.Suspension through exceed the speed limit under 100,000 × g from
Heart 1h enrichments, and cell mass is resuspended in 16mL NaPi containing 20mM（pH7.8）, 500mM NaCl, 1% triton x-100 it is slow
In fliud flushing.The cell extract of suspension carries out ultracentrifugation 1h under 100,000 × g, and by the suspension of enrichment for external
Analysis.All proteins extraction step carries out on ice or at 4 DEG C.
Analyzed in vitro：
The bioactivity of compound is evaluated using fluorescence-based analysis, to which quantitative arachidonic base 7- amino, 4 methyl are fragrant
Legumin amide（AAMCA）, fatty amide hydrolase（FAAH）Fluorogenic substrate hydrolysis（Anal Biochem.2005、343
(1)：143-51）.In 96 hole black polystyrene plates（Greiner Bio-one, Germany）In divided with 200 μ L volumes
Analysis.Each reaction is by containing 50mM HEPES, 1mM EDTA and 0.1%BSA（PH7.4）Analysis buffer in people's fatty acyl aqueous amine
Solve enzyme（FAAH）Albumen and 10 μM of AAMCA are constituted.With the inhibitor of 2 μ L various concentrations in DMSO（The final concentration 1% of DMSO）
Oscillation while incubation reaction 1min and in 50min monitor kinetics model in fluorescence increase.In excitation wavelength 355nm
Down and under 460nm transmittings, Flexstation III microplate reader is used（Molecular Devices, Sunnyvale, CA）It surveys
Measure the increase of fluorescence.The reaction rate of function used as inhibitor concentration measures the IC of inhibitor50.Use Graph
PadPrism（Graph Pad Software Inc., San Diego, CA）Analyze data.Rat fat acyl is utilized as described above
Amine hydrolase（FAAH）Albumen and 10 μM of AAMCA substrates evaluate compound to rat fat hydroamidase（FAAH）Activity.
, 1 the compounds of this invention of table is to people and rat FAAH inhibitory activity.
| hFAAH IC50（nM） | rFAAH IC50（nM） | |
| Embodiment 1 | 28 | 110 |
| Embodiment 2 | 6 | 127 |
| Embodiment 3 | 2 | 73 |
| Embodiment 4 | 17 | 82 |
| Embodiment 5 | 22 | 86 |
| OL-135 | 10 | 79 |
Inhibit to live well the result shows that the compound by test has people and rat fat hydroamidase
Property, IC50Value is within the scope of 2nM to 127nM, the IC of embodiment 350Value is 2nM.Positive control OL-135 is to people and rat fat
The inhibitory activity IC of fat hydroamidase50Value is respectively 10nM and 79nM.Illustrate that the compound of the present invention can be used as fatty acyl
Follow-up research and development of the amine hydrolase inhibitor for the preparation of related drugs.
Claims (6)
1. a kind of inhibitors of fatty amide hydrolase, structural formula are
Wherein, X is selected from C；R1Selected from H；R2Selected from H；R3Selected from H.
2. the synthetic route of inhibitors of fatty amide hydrolase as described in claim 1 is
。
3. inhibitors of fatty amide hydrolase as described in claim 1 for treat, prevent or auxiliary treatment mammal and
Application in people in adjusting fatty amide hydrolase relevant disease.
4. application of the inhibitors of fatty amide hydrolase as described in claim 1 in the drug for the treatment of pain.
5. a kind of composition, which is characterized in that including inhibitors of fatty amide hydrolase described in claim 1 and pharmaceutically may be used
The auxiliary material of receiving.
6. composition as claimed in claim 4, which is characterized in that inhibitors of fatty amide hydrolase described in claim 1
As sole active agent.
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| CN201810457983.XA CN108409727A (en) | 2017-10-25 | 2017-10-25 | A kind of inhibitors of fatty amide hydrolase and preparation method thereof |
| CN201711010260.7A CN107602550B (en) | 2017-10-25 | 2017-10-25 | A kind of inhibitors of fatty amide hydrolase and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008023720A1 (en) * | 2006-08-23 | 2008-02-28 | Astellas Pharma Inc. | Urea compound or salt thereof |
| JO3598B1 (en) * | 2006-10-10 | 2020-07-05 | Infinity Discovery Inc | Boronic acids and esters as inhibitors of fatty acid amide hydrolase |
| TWI434842B (en) * | 2008-07-14 | 2014-04-21 | Astellas Pharma Inc | Azole compounds |
| EP2509978A1 (en) * | 2009-12-11 | 2012-10-17 | E.I. Du Pont De Nemours And Company | Azocyclic inhibitors of fatty acid amide hydrolase |
| WO2015200682A1 (en) * | 2014-06-25 | 2015-12-30 | Vanderbilt University | Substituted 4-alkoxypicolinamide analogs ds mglur5 negative allosteric modulators |
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Application publication date: 20180817 |