CN108912112A - A kind of compound, preparation method and its application in treatment pain - Google Patents
A kind of compound, preparation method and its application in treatment pain Download PDFInfo
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- CN108912112A CN108912112A CN201810924802.XA CN201810924802A CN108912112A CN 108912112 A CN108912112 A CN 108912112A CN 201810924802 A CN201810924802 A CN 201810924802A CN 108912112 A CN108912112 A CN 108912112A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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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
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- 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]
Abstract
The invention discloses a kind of compound, preparation method and its application in treatment pain, the structural formula of compound to beWherein, R1、R2、R3It is independently selected from selected from-H ,-F or-NO2.Compound by test has inhibitory activity well, IC of the one~example IV of embodiment to hFAAH for people and rat fat hydroamidase50Value is within the scope of 2nM to 4nM, to the IC of rFAAH50Value has selective inhibitory activity within the scope of 106nM to 131nM, to people's fatty amide hydrolase.Illustrate that the compounds of this invention can be used for treating pain, the pain can be pain caused by postoperative pain, chronic pain, cancer pain, cancer chemotherapy, neuralgia, nociception pain, inflammatory pain.
Description
Technical field
The invention belongs to the combinations in the fields such as pharmaceutical chemistry, Pharmaceutical Analysis, pharmaceutical preparation and pharmaceutical activity test, are related to one
Kind compound, preparation method and its application in treatment pain, the pain are postoperative pain, chronic pain, cancer pain, cancer
Pain caused by disease chemotherapy, neuralgia, nociception pain, inflammatory pain.
Background technique
Pain is that body comes to harm and a kind of caused by sexual stimulus unhappy feels and emotional experience.Pain has been cited as
The fifth-largest vital sign after breathing, pulse, blood pressure, body temperature.At present major part hospital individually set up Pain Management with
Alleviate patient's sufferings, pain is also Neurology big event.
Fatty amide hydrolase (fatty acid amide hydrolase, FAAH) is a kind of inner membrance amide signal family
Protease, be many biologically active fatty acid amide courier lipid moleculars in organism (fatty acid amides,
FAAs major catalytic) hydrolyzes metabolic enzyme.Research shows that FAAH takes part in the regulation of many A signal pathways, with pain, anxiety, sleep
The occurrence and development of a variety of diseases such as dormancy disorder have close relationship.It is currently based on FAAH signal path treatment pain and has become one
A research hotspot.
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 rouge
The hydrophobic region of fat acid chain is known as fatty acid chain combined area (acyl chain-binding pocket, ABP), and 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 be in clinical and preclinical bioactivity survey
The examination stage.According to Thomson Reuters Cortellis statistics of database, there are multiple drugs to be in conceptual phase at present.
Summary of the invention
It is an object of the present invention to designing and providing a kind of novel compound, structure is shown in formula I
Wherein, R1、R2、R3It is independently selected from selected from-H ,-F or-NO2。
Further, novel Formula I specific structure is selected from：
Another object of the present invention is to provide the synthetic routes of novel Formula I a kind of：
Further, specific synthesis step is：
1) amidation process, generationization occur in a suitable solvent, compound 1 and 2,2- dimethoxy-ethane -1- amine
Close object 2；
2) nucleophilic substitution generation ether namely compound 3 occur for the hydroxyl in compound 2 and bromomethyl benzene；
3) compound 3 hydrolyzes under the action of certain density hydrochloric acid, generates compound 4；
4) cyclization generation compound 5 occurs for compound 4；
5) compound 5 reacts with corresponding amine generate corresponding final product again.
Further, solvent can be methylene chloride, 1,2- dichloroethanes, second eyeball, N, N- dimethyl in the step 1)
Formamide (DMF), tetrahydrofuran, ethyl acetate, toluene, dimethylbenzene or other suitable solvents, preferably tetrahydrofuran.
Further, the range of choice of concentration of hydrochloric acid is 1mol/L~5mol/L in the step 3), preferably 2mol/L.
Another object of the present invention is to provide a kind of Formula I or its salt to prevent, treat or assist in the treatment of lactation
Application in animal and people in fatty amide hydrolase related disease, the disease such as pain, including acute and chronic, such as
Pain caused by postoperative pain, chronic pain, cancer pain, cancer chemotherapy, neuralgia, nociception pain, inflammatory pain, backache, by
The pain as caused by the disease in following various sources：Diabetic neuropathy, the thermophilic nervous system type including human immunodeficiency virus
Such as post herpetic neuralgia of pain caused by viral disease, shingles zoster；Polyneuropathy, neurotoxicity, mechanical neurotrosis, wrist
Pipe syndrome, amynologic mechanism such as multiple sclerosis.
Another object of the present invention is to a kind of compositions, including the Formula I and pharmaceutically acceptable auxiliary material.
Further, inhibitors of fatty amide hydrolase described in the composition is as sole active agent.
Obviously, above content 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 embodiment
Embodiment one：The conjunction of 2- (8- (benzyloxy) -7- (3- methoxymethyl-pyrrolidin -1- base) quinoline -2- base) oxazole
At
1, the bromo- N- of 7- (2,2- dimethoxy-ethyl) -8-hydroxyquinoline -2- formamide synthesis：
At room temperature, to the bromo- 8-hydroxyquinoline -2- carboxylic acid (compound 1) (77.74g, 290mmol) of 7- in ethyl acetate
Thionyl chloride (41.40g, 348mmol) is added in the suspension of (200mL), and is heated to reflux 3 hours.Reaction mixture is cold
But it to room temperature, is diluted with tetrahydrofuran (50mL), 2,2- dimethoxy-ethane -1- amine is then added dropwise at room temperature
Tetrahydrofuran (250mL) solution of (42.69g, 406mmol) and triethylamine (110mL, 789mmol).Then it is stirred at 40 DEG C
It mixes reaction mixture 1 hour, is cooled to room temperature, 300mL water is added and is extracted with ethyl acetate.Organic layer is successively used
2mol/L hydrochloric acid, 10% wet chemical and water are washed.Solvent under reduced pressure is concentrated to dryness, the crude product of 89.20g is obtained
The bromo- N- of 7- (2,2- dimethoxy-ethyl) -8-hydroxyquinoline -2- formamide (compound 2), yield 86.6%, without purifying, directly
It connects in next step synthetic reaction.1H-NMR(400MHz,CDCl3)δ:3.32(d,2H),3.40(s,6H),4.70(t,1H),
5.43(s,1H),6.62(s,1H),7.44(d,1H),7.60(d,1H),7.71(d,1H),8.38(d,1H).13C-NMR
(125MHz,CDCl3)δ:46.79,55.35,102.99,105.60,117.73,122.31,129.02,130.45,132.51,
133.38,142.91,151.85,166.77.LC-MS(ESI,pos,ion)m/z:356[M+H].
2, the synthesis of the bromo- N- of 8- (benzyloxy) -7- (2,2- dimethoxy-ethyl) quinoline-2-formamide：
By compound 2 (89.20g, 251.13mmol), potassium carbonate (35.93g, 260.0mmol), potassium iodide (4.65g,
28.00mmol), bromomethyl benzene (45.84g, 268.00mmol) is dissolved in n,N-Dimethylformamide (50.00mL), then
Reaction mixture is stirred 6 hours at 90 DEG C.It is under the conditions of ice-water bath that reaction mixture is cooling, into reaction mixture according to
Secondary addition 2mol/L hydrochloric acid (23.00mL), MeOH (25.00mL), water (25.00mL).The crystalline solid being collected by filtration, obtains
To white crystals 8- (benzyloxy) -7- bromo- N- (2,2- dimethoxy-ethyl) quinoline-2-formamide of 101.77g, yield is
91.0%.1H-NMR(400MHz,CDCl3)δ:3.30(d,2H),3.38(s,6H),4.97(t,1H),5.13(s,2H),6.93
(s,1H),7.24-7.46(m,6H),7.56(d,1H),7.64(d,1H),8.21(d,1H).13C-NMR(125MHz,CDCl3)
δ:46.79,55.35,74.56,102.99,112.40,120.61,121.87,128.16,128.17,128.19,129.01,
130.42,133.22,137.56,139.87,143.56,152.39,166.77.LC-MS(ESI,pos,ion)m/z:446[M+
H].
3, the synthesis of the bromo- N- of 8- (benzyloxy) -7- (2- oxoethyl) quinoline-2-formamide：
Compound 3 (101.77g, 228.54mmol) is dissolved in tetrahydrofuran (120mL) solution, then into this solution
The hydrochloric acid (116mL, 231mmol) of 2mol/L is added, and is stirred 3 hours at 50 DEG C.Then reaction mixture is cooled to room
Temperature adds water (90mL), is extracted with ethyl acetate, organic layer is then washed with water twice.It is different with two after solvent is concentrated under reduced pressure
Propyl ether mashing, obtains white crystal 8- (benzyloxy) -7- bromo- N- (2- oxoethyl) quinoline-2-formamide (chemical combination of 72.81g
Object 4), yield 79.8%.1H-NMR(400MHz,CDCl3)δ:3.88(d,1H),4.13(d,1H),5.16(s,2H),6.10
(s,1H),7.28-7.50(m,6H),7.60(d,1H),7.68(d,1H),8.25(d,1H),9.72(t,1H).13C-NMR
(125MHz,CDCl3)δ:42.75,74.56,112.40,120.61,121.87,128.16,128.17,128.19,129.01,
130.42,133.22,137.56,139.87,143.56,152.39,165.70,194.28.LC-MS(ESI,pos,ion)m/
z:400[M+H].
4, the synthesis of 2- (8- (benzyloxy) -7- bromoquinoline -2- base) oxazole：
At room temperature, to the compound 4 (72.81g, 182.37mmol) and carbon trichloride being dissolved in acetonitrile (60mL)
Triphenylphosphine (95.67g, 364.74mmol) is added in the suspension of (86.34g, 364.74mmol), then stirs 25 minutes,
It is added triethylamine (50.70mL, 364.74mmol).Then reaction mixture is stirred at room temperature 3 hours, and at 50 DEG C again
Then stirring 3 hours reheats reflux 8 hours.After reaction mixture is cooled to room temperature, it is added water (50mL), and use acetic acid
Ethyl ester extraction.Organic layer is successively used into salt water and water washing.After solvent is concentrated under reduced pressure, is recrystallized, obtained with methanol/water
White crystals 2- (8- (benzyloxy) -7- bromoquinoline -2- base) oxazole (compound 5) of 59.10g, yield 85.0%.1H-NMR
(400MHz,CDCl3)δ:5.16(s,2H),7.15(d,1H),7.28-7.50(m,7H),7.60(d,1H),7.65(d,1H),
7.99(dd,1H).13C-NMR(125MHz,CDCl3)δ:74.56,112.40,120.61,120.92,128.16,128.19,
129.01,129.98,130.38,130.42,137.21,137.56,139.05,140.05,143.46,152.39,
157.98.LC-MS(ESI,pos,ion)m/z:382[M+H].
5, the synthesis of 2- (8- (benzyloxy) -7- (3- methoxymethyl-pyrrolidin -1- base) quinoline -2- base) oxazole：
Under an argon atmosphere, acid chloride is added into the toluene suspension of 3- methoxymethyl-pyrrolidin (52mmol)
Toluene (37mL) solution, the two adamantane butyl phosphines of (2.40g), p-methyl benzenesulfonic acid sodium salt (3.90g), sodium tert-amyl alcohol (11.8g)
(7.70g), and be stirred at room temperature 1 hour.In reaction suspension, under the conditions of ice-water bath be added compound 5 (19.10g,
50.10mmol) with toluene (33mL), then it is heated to reflux 4 hours.Reaction mixture is cooled to room temperature after the reaction was completed, is added
Enter 2mol/L hydrochloric acid (37.5mL).The precipitating to be formed is collected by filtration, obtains the light brown crystalline 2- (8- (benzyloxy)-of 18.11g
7- (3- methoxymethyl-pyrrolidin -1- base) quinoline -2- base) oxazole, yield 87%.1H-NMR(400MHz,CDCl3)δ:1.42
(m,1H),1.74(m,1H),2.03(m,1H),2.89(q,1H),3.12(m,1H),3.31-3.51(m,5H),3.74-3.81
(m,2H),5.16(s,2H),6.78(dd,1H),7.15(d,1H),7.27-7.48(m,6H),7.60(d,1H),7.85(dd,
1H),8.10(d,1H).13C-NMR(125MHz,CDCl3)δ:29.98,42.33,52.92,56.88,58.75,73.92,
74.56,113.39,119.16,123.94,128.16,128.19,129.01,130.13,130.38,136.38,137.21,
137.56,138.02,138.52,144,146.4,157.98.LC-MS(ESI,pos,ion)m/z:416[M+H].
Embodiment two：2- (8- (benzyloxy) -7- (the fluoro- 4- methoxymethyl-pyrrolidin -1- base of 2-) quinoline -2- base) is disliked
The synthesis of azoles
Under an argon atmosphere, acetic acid is added into the toluene suspension of the fluoro- 4- methoxymethyl-pyrrolidin (52mmol) of 2-
Palladium (2.40g), p-methyl benzenesulfonic acid sodium salt (3.90g), sodium tert-amyl alcohol (11.8g) toluene (37mL) solution, two adamantane butyl
Phosphine (7.70g), and be stirred at room temperature 1 hour.In reaction suspension, under the conditions of ice-water bath be added compound 5 (19.10g,
50.10mmol) with toluene (33mL), then it is heated to reflux 4 hours.Reaction mixture is cooled to room temperature after the reaction was completed, is added
Enter 2mol/L hydrochloric acid (37.5mL).The precipitating to be formed is collected by filtration, obtains the light brown crystalline 2- (8- (benzyloxy)-of 18.68g
7- (the fluoro- 4- methoxymethyl-pyrrolidin -1- base of 2-) quinoline -2- base) oxazole, yield 86%.LC-MS(ESI,pos,ion)m/
z:434[M+H].
Embodiment three：2- (8- (benzyloxy) -7- (2- nitro -4- methoxymethyl-pyrrolidin -1- base) quinoline -2- base)
The synthesis of oxazole
Under an argon atmosphere, second is added into the toluene suspension of 2- nitro -4- methoxymethyl-pyrrolidin (52mmol)
Sour palladium (2.40g), p-methyl benzenesulfonic acid sodium salt (3.90g), toluene (37mL) solution of sodium tert-amyl alcohol (11.8g), two adamantane fourths
Base phosphine (7.70g), and be stirred at room temperature 1 hour.In reaction suspension, compound 5 is added under the conditions of ice-water bath
(19.10g, 50.10mmol) and toluene (33mL), is then heated to reflux 4 hours.Reaction mixture is cooled to after the reaction was completed
Room temperature is added 2mol/L hydrochloric acid (37.5mL).The precipitating to be formed is collected by filtration, obtains the light brown crystalline 2- (8- (benzyl of 19.15g
Oxygroup) -7- (2- nitro -4- methoxymethyl-pyrrolidin -1- base) quinoline -2- base) oxazole, yield 83%.LC-MS(ESI,
pos,ion)m/z:461[M+H].
Example IV：2- (8- (benzyloxy) -7- (2- nitro -3- methoxymethyl-pyrrolidin -1- base) quinoline -2- base)
The synthesis of oxazole
Under an argon atmosphere, second is added into the toluene suspension of 2- nitro -3- methoxymethyl-pyrrolidin (52mmol)
Sour palladium (2.40g), p-methyl benzenesulfonic acid sodium salt (3.90g), toluene (37mL) solution of sodium tert-amyl alcohol (11.8g), two adamantane fourths
Base phosphine (7.70g), and be stirred at room temperature 1 hour.In reaction suspension, compound 5 is added under the conditions of ice-water bath
(19.10g, 50.10mmol) and toluene (33mL), is then heated to reflux 4 hours.Reaction mixture is cooled to after the reaction was completed
Room temperature is added 2mol/L hydrochloric acid (37.5mL).The precipitating to be formed is collected by filtration, obtains the light brown crystalline 2- (8- (benzyl of 18.23g
Oxygroup) -7- (2- nitro -3- methoxymethyl-pyrrolidin -1- base) quinoline -2- base) oxazole, yield 79%.LC-MS(ESI,
pos,ion)m/z:461[M+H]。
Test example：People and rat fat amide hydrolysis enzyme inhibition activity
For the compounds of this invention to people and rat fat hydroamidase (FAAH) inhibitory activity, test method is same
CN103958473B, unless otherwise stated, all reagents are purchased from Sigma.It is summarized as follows：
Material and reagent：
For the people of analysis and rat fat hydroamidase (FAAH) gene by Patricelli etc.
(Biochemistry.1998,37 (43), 15177-87) description.Fatty amide hydrolase (FAAH) gene that transmembrane domain is deleted
It is cloned into pET15b (Novagen, #69661) (people FAAH)/pET28a (Novagen, #69864-3) (rat FAAH gene) matter
It is expressed in grain and in Escherichia coli (Ecoli) BL21DE3.Companion's egg in pGR07 plasmid (Takara Bio Inc, Japan)
White groEL-groES and fatty amide hydrolase (FAAH) are co-expressed, so as to improve expression in escherichia coli protein it is molten
Xie Du.It is recorded in such as Mileni (Proc NatlAcad Sci USA.2008,105 (35), 12820-4), to express simultaneously
Enrichment protein.In short, using arabinose (2mM) and isopropyl ss-D-1- thiogalactoside (IPTG) (1mM) at room temperature
Induce the bacterial cultures 20h in LB culture medium (Luria Broth) (2L).Culture is centrifuged 10min at 1200 × g,
And by cell mass (cell pellet) be resuspended in 100mL NaPi containing 20mM (pH7.4), 100mM NaCl, nuclease (500u),
In the buffer of Aprotinin (1 μ g/mL) and leupeptin (1 μ g/mL).Pass through sonic method (Amp 20%, pulse 15s × 15, ice
On) lytic cell, and cell fragment is removed by being centrifuged 20min under 5000 × g.Suspension exceeded the speed limit under 100,000 × g from
The heart 1h enrichment, and by cell mass be resuspended in 16mL NaPi containing 20mM (pH7.8), 500mM NaCl, 1% triton x-100 delay
In fliud flushing.The cell extract of suspension carries out ultracentrifugation 1h under 100,000 × g, and the suspension of enrichment is used in vitro
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, thus quantitative arachidonic base 7- amino, 4 first
Butylcoumariii amide (AAMCA), fatty amide hydrolase (FAAH) fluorogenic substrate hydrolysis (Anal Biochem.2005,
343(1)：143-51).With the progress of 200 μ L volumes in 96 hole black polystyrene plates (Greiner Bio-one, Germany)
Analysis.Each reaction by HEPES containing 50mM, 1mM EDTA and 0.1%BSA (PH7.4) analysis buffer in people's fatty acid amide
Hydrolase (FAAH) albumen and 10 μM of AAMCA are constituted.With the inhibitor (final concentration of DMSO of 2 μ L various concentrations in DMSO
1%) oscillation while incubation reaction 1min and in 50min monitor kinetics model in fluorescence increase.In excitation wavelength
Under 355nm and 460nm transmitting under, using Flexstation III microplate reader (Molecular Devices, Sunnyvale,
CA the increase of fluorescence) is measured.The reaction rate of function used as inhibitor concentration measures the IC of inhibitor50.It uses
Graph PadPrism (Graph Pad Software Inc., San Diego, CA) analyzes data.Rat is utilized as described above
Fatty amide hydrolase (FAAH) albumen and 10 μM of AAMCA substrate evaluation compounds are 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) | |
| EmbodimentOne | 3 | 106 |
| Embodiment two | 4 | 113 |
| Embodiment three | 2 | 122 |
| Example IV | 2 | 131 |
| OL-135 | 12 | 83 |
Inhibit to live well the result shows that the compound by test has people and rat fat hydroamidase
Property, inhibitory activity IC of the positive control OL-135 to people and rat fat hydroamidase50Value is respectively 12nM and 83nM.Implement
IC of the one~example IV of example to hFAAH50Value is within the scope of 2nM to 4nM, to the IC of rFAAH50Value is in 106nM to 131nM model
In enclosing, there is selective inhibitory activity to people's fatty amide hydrolase.Illustrate that the compound of the present invention can be used as fatty acid amide
Hydrolase inhibitor carries out subsequent research and development, the disease such as pain paid close attention in R&D process, including acute and chronic, such as
Pain caused by postoperative pain, chronic pain, cancer pain, cancer chemotherapy, neuralgia, nociception pain, inflammatory pain, backache, by
The pain as caused by the disease in following various sources：Diabetic neuropathy, the thermophilic nervous system type including human immunodeficiency virus
Such as post herpetic neuralgia of pain caused by viral disease, shingles zoster；Polyneuropathy, neurotoxicity, mechanical neurotrosis, wrist
Pipe syndrome, amynologic mechanism such as multiple sclerosis.
Claims (5)
1. a kind of compound, its structure of compound is shown in formula I
Wherein, R1、R2、R3It is independently selected from selected from-H ,-F or-NO2。
2. the synthetic route of Formula I as described in claim 1, it is characterized in that being, synthetic route is
3. Formula I as described in claim 1 or its salt are fatty in preventing, treating or assisting in the treatment of mammal and people
Application in hydroamidase related disease.
4. the application of Formula I as described in claim 1 or its salt in the drug for the treatment of pain.
5. application as claimed in claim 4, characterized in that the pain is selected from postoperative pain, chronic pain, cancer pain, cancer
Pain caused by chemotherapy, neuralgia, nociception pain, inflammatory pain.
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