CN106317059A - Novel cannabinoid receptor 2(CB2) agonist - Google Patents
Novel cannabinoid receptor 2(CB2) agonist Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a propanamide coupled piperidinoxadiazole and imidazo[1,2-a]pyrazine derivative shown as a formula I and/or medicinal salts thereof and a preparation method thereof, as well as a pharmaceutical composition comprising the compound. The compound shown as the formula I is a potential cannabinoid receptor 2(CB2) agonist and can be used for treating and/or preventing diseases such as inflammation, inflammatory bowel diseases, glaucoma, diabetes, nephropathy, cardiomyopathy and the like. The structural formula is as shown in the specification, wherein R1 is aryl and heteroaryl; and R2 is H, (C1-C6) linear alkyl or branched alkyl.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to the piperidines of a kind of propionic acid amide. connection described in claim
Base diazole and imidazo [1,2-a] pyrazine compounds and physiologically acceptable salt thereof, their preparation method and it
Prevention and/or treatment pain, inflammation, inflammatory bowel, glaucoma, diabetes, diabetic retinopathy, tremulous pulse medicated porridge sample
Hardening, age-related macular degeneration, acute hepatic failure, hepatic fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosing, scarce
Blood-reperfusion injury, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephritis
Disease, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, hot injury, burn, hypertrophic scar, gingivitis are sent out
Use in Cannabined receptor 2 (CB2) the agonist relevant diseases such as heat, liver cirrhosis or tumor, osteoporosis, neural degeneration, apoplexy
On the way.
Technical background
Cannabinoid (cannabinoid, CB) is to play therapeutical effect and mentalistic chemical substance in Fructus Cannabis, 1964,
The main active tetrahydro-cannabinolic acid to cannabis plant first such as Gaoni, has carried out the confirmation of separation and stereochemical structure
(Gaoni,Y.et.al,J.Am.Chem.Soc,1964,86,1646).Researchers separate again and synthesis obtains a series of subsequently
Cannabinoids compound (Felder, C.C.et.al, Mol.Interv, 2006,6,149).Traditional Cannabinoids chemical combination owner
Including five classes: 1, the classical Cannabinoids compound with tetrahydro-cannabinolic acid as representative, this compounds is from natural plants
Cannabinoid extracted and the like, three ring parent nucleus are its structural features；2, in AEA and 2-AG as representative
Source property cannabinoid；3, the non-classical Cannabinoids compound with CP55940 as representative, this compounds is opening of classical cannabinoid
Ring derivatives；4, the amino alkyl indole compounds with WIN55212-2 as representative；5, the diaryl with SR141716A as representative
Pyrazole compound (Howlett, A.C.et.al, Pharmacol.Rev, 2002,54,161).
Meanwhile, the mechanism of action of Cannabinoids compound has been also carried out studying widely by people.Cannabinoid is made
For Cannabined receptor (cannabinoid receptor, CB-R) to realize its physiologically active, study proof, cannabinoid at present
Receptor includes two hypotypes: Cannabined receptor 1 (cannabinoid receptor 1, CB1 receptor) and Cannabined receptor 2
(cannabinoid receptor 2, CB2).Nineteen ninety, the successful clone in rat cerebral cortex cDNA library such as Matsuda
Go out CB1 receptor (Matsuda, L.A.et.al, Nature, 1990,346,561)；CB2 receptor then existed by Munro etc. in 1993
Successful clone in the promyelocytic leukemia protein HL60CDNA library of the mankind (Munro, S.et.al, Nature, 1993,
365,61).CB1 receptor and CB2 receptor belong to g protein coupled receptor (G-protein coupled receptor, GPCR) together
Rhodopsin sample family, has typical 7 sections of a-spiral transmembrane structure, the aminoacid sequence that two kinds of receptors are complete have 44% same
Source property, the aminoacid sequence in relatively conservative both cross-film districts have 68% homology (Pacher, P.et.al,
Pharmacol.Rev,2006,58,389).Wherein, CB2 mainly at immune cell, such as macrophage and T-cell and
Gastronintestinal system periphery is expressed, and CB2 receptor is also widely distributed in brain, and wherein it is principally found in microglia and non-neuron
On.
The compound that CB2 receptor stimulating agent is relevant has shown preferable activity in numerous disease, these disease bags
Include pain (Beltramo, M.Mini Rev Med Chem, 2009,9,11), inflammation (Cabral, G.A.et.al, J Leukoc
Biol, 2005,78,1192), colitis (Lin Sisi etc., Chinese Journal of Pathophysiology, 2015,10,195), glaucoma
(Hampson, A.J.et.al, PNAS, 1998,95,8268), hepatic fibrosis (Julien,
B.et.al.Gastroenterology, 2005,128,742), cerebral ischemia reperfusion injury (Lopez, R.A, Cereb
Cortex,2011,21,2046；Sun Jing etc., China Medicine University's journal, 2013,44,167), tumor (Deng Yuanfei, cure by Guangdong
Learn, 2016,8,1109), cardiomyopathy (recklessly literary composition magnitude, heart journal, 2014,3,265) etc..
The diversified clinical value of CB2 receptor stimulating agent demonstrates its bright prospects at field of medicaments, but
Up to the present, there is no CB2 receptor stimulating agent becomes marketed drug, thus, it is found that novel high-activity, high selectivity and having relatively
The CB2 receptor stimulating agent of good druggability has very important significance for this field.
Summary of the invention
The present invention describes compound of formula I, and/or their officinal salt
Wherein, R1For aryl, heteroaryl, R2For H, (C1-C6) straight or branched alkyl.
Preferably, R1Selected from 2-Trifluoromethoxyphen-l, 4-Trifluoromethoxyphen-l, 2,4-bis-Trifluoromethoxyphen-l,
2-methoxyphenyl, 4-methoxyphenyl, 2,4-Dimethoxyphenyl, 2-aminomethyl phenyl, 4-aminomethyl phenyl, 2,4-dimethyl benzene
Base, 2-fluorophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 2-chlorphenyl, 4-chlorphenyl, 2,4 dichloro benzene base, 2-pyridine radicals；With
Time R2Selected from H, methyl.I.e. for R1For substituent group, representational example is as follows,
Asterisk (*) represents that the carbon atom of this key and piperidine ring 4 is connected.
The invention still further relates to compound of formula I and/or its officinal salt for preventing and/or treat pain, inflammation, inflammatory bowel
Disease, glaucoma, diabetes, diabetic retinopathy, atherosclerosis, age-related macular degeneration, acute hepatic failure,
Hepatic fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosing, ischemia reperfusion injury, acute allograft rejection,
Chronic allograft nephropathy, diabetic nephropathy, glomerule nephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction,
Systemic sclerosis, hot injury, burn, hypertrophic scar, gingivitis heating, liver cirrhosis or tumor, osteoporosis, neural degeneration, finally
In.
The invention still further relates to pharmaceutical preparation (or pharmaceutical composition), its contain effective dose at least one compound of formula I and/
Or its officinal salt, the excipient of physiology's tolerance and carrier, and also have other additives and/or other activity in due course
Composition.Medicine can be Orally administered, such as with pill, tablet, spraying sheet, coated tablet, granule, hard and Perle, molten
Liquid, syrup, Emulsion, suspensoid or aerosol mixtures form.But, use and may be carried out as follows: per rectum be administered, such as with
Suppository form；Or parenteral, such as through intravenous, intramuscular or subcutaneous with injection solution or infusion solution, microcapsule, implant
Or implant the form of rod；Or percutaneous or topical, such as with ointment, solution or tincture form；Or with other administrations,
Such as with aerosol or form of nasal sprays.
The pharmaceutical preparation of the present invention is by known per se and prepare, except formula in the way of being known to those skilled in the art
Outside I and/or their officinal salt and/or their prodrug, use pharmaceutically useful inert inorganic and/or organic carrier
Material and/or additive.For the preparation of pill, tablet, coated tablet and hard gelatin capsule, may use such as lactose,
Corn starch or derivatives thereof, Talcum, stearic acid or its salt etc..The carrier mass of Perle and suppository have such as fat,
Wax, semisolid and liquid polyol, natural or fixed oil etc..It is suitable for preparing solution, such as injection solution or Emulsion or syrup
The carrier mass of agent has such as water, saline, alcohol, glycerol, polyhydric alcohol, sucrose, Nulomoline, glucose, vegetable oil etc..It is suitable for
Microcapsule, implant or the carrier mass of implantation rod, the copolymer of such as glycolic and lactic acid.Pharmaceutical preparation usually contains about 0.5
To the compound of formula I of about 90% weight and/or their officinal salt and/or their prodrug.Activity one-tenth in pharmaceutical preparation
The amount of compounds of formula I and/or their officinal salt and/or their prodrug normally about 0.5 is to about 1000mg, preferably from about 1
To about 500mg.
In addition to the active component of Formulas I and/or their officinal salt and carrier mass, pharmaceutical preparation can be containing one
Or multiple additives, such as filler, disintegrating agent, binding agent, lubricant, wetting agent, stabilizer, emulsifying agent, preservative, sweet taste
Agent, coloring agent, correctives, aromatic, thickening agent, diluent, buffer substance, solvent, solubilizing agent, the examination of acquisition depot effect
Agent, the change salt of osmotic pressure, coating materials or antioxidant.They can also containing two or more compound of formula I and/or they
Officinal salt.When pharmaceutical composition contains two or more compound of formula I, the selection to individual compound can be according to medicine
The specific overall pharmacological property of thing preparation.Such as, the height potent compound that acting duration is shorter can with effect relatively
Low long-acting compound combination.The motility allowed for substituent group in compound of formula I selects makes it possible to compound
Biology and physicochemical properties carry out numerous control, it is possible to select this kind of required compound.Additionally, except at least one
Planting outside compound of formula I and/or its officinal salt, pharmaceutical preparation also can contain one or more other treatments or preventative work
Property composition.
When using compound of formula I, dosage can change, agent in grace period and according to known to conventional and doctor
Amount should be suitable for the individual instances of every kind example.It depends on particular compound, the character of treated disease such as applied
With the order of severity, method of application and scheme or treated is acute or chronic disease or whether prevent.The agent being suitable for
Clinical method known to the available medical domain of amount is set up.It is said that in general, obtain results needed in the adult weigh about 75kg
Daily dose be about 0.01 to about 100mg/kg, preferably from about 0.1 to about 50mg/kg, especially about 0.1 to about 10mg/kg (every kind of feelings
With mg/kg weighing machine under condition).Especially in the case of using relatively large amount, if daily dose can be divided into stem portion, such as 2,3
Or 4 part use.Generally, according to individual behavior, it may be necessary to deviate described daily dose up or down.
Additionally, compound of formula I can be used as preparing other compounds, the particularly synthetic mesophase of other drug active component
Body, it can be by compound of formula I such as by introducing substituent group or modifying functional group's acquisition.
In most of the cases, the reactant mixture of the finalization compound containing Formulas I or intermediate is carried out post processing, as
Fruit is necessary, by product by conventional method purification well known by persons skilled in the art.Such as, synthesized compound may utilize
Known to method such as crystallization, chromatograph or reversed phase high-performance liquid chromatography (RP-HPLC) or based on such as compound size, electric charge or
Other separation methods hydrophobic are purified.Similarly, the method known such as NMR, IR and mass spectrography (MS) can be used for characterizing
The compounds of this invention.
Therefore, following example are the parts of the present invention, are used for illustrating and the unrestricted present invention.
It should be noted that, the modification of the non-substantial effect present invention various embodiment activity is included in disclosed herein
The scope of the invention in.
Embodiment:
The preparation of the first step: 4-[2-(trifluoromethoxy) phenyl] piperidines-1-nitrile
By 4-[2-(trifluoromethoxy) phenyl] piperidines (10.0g, 40.8mmol), potassium carbonate (11.1g, 80.2mmol) adds
In 100mL methylene chloride/water (1:1), stirring, it is cooled to 0 DEG C.By be dissolved in 20mL dichloromethane cyano group bromine (5.3g,
50.0mmol) it is slowly dropped in above-mentioned solution, at 0 DEG C, reacts 30min, recover to room temperature to continue reaction 2h, separate organic layer, use
Saturated sodium bicarbonate solution, saturated nacl aqueous solution washing organic layer, anhydrous magnesium sulfate is dried, concentrating under reduced pressure organic facies, slightly produces
Product obtain 4-[2-(trifluoromethoxy) phenyl] piperidines-1-nitrile 8.9g with silica gel column chromatography (petrol ether/ethyl acetate=7/3) and (receive
Rate: 81%).
1H-NMR(400MHz,CDCl3): δ 7.12-7.03 (m, 2H), 6.69-6.51 (m, 2H), 3.52 (d, J=
12.0Hz,2H),3.17-3.04(m,2H),2.70-2.68(m,1H),1.98-1.83(m,2H),1.70-1.61(m,2H)；
LC/MS(M+1)+=271.1.
Second step: the preparation of (E)-N-hydroxyl-4-[2-(trifluoromethoxy) phenyl] piperidines-1-carbonamidine
4-[2-(trifluoromethoxy) phenyl] piperidines-1-nitrile (8.0g, 30.0mmol) is dissolved in isopropanol/water (4/1)
In 30mL, under room temperature, add oxammonium hydrochloride. (10.4g, 150.0mmol), stir 5h at 90 DEG C, be cooled to room temperature, add in solution
Entering 6N HCl/water solution, ether washs, and adjusts pH value to extract to alkalescence, ether, collect organic aqueous phase with aqueous sodium carbonate
Phase, be dried, concentrating under reduced pressure obtain (E)-N-hydroxyl-4-[2-(trifluoromethoxy) phenyl] piperidines-1-carbonamidine 7.9g (yield:
87%).LC/MS(M+1)+=304.1.
3rd step: ethyl-3-[3-[4-[2-(trifluoromethoxy) phenyl] piperidin-1-yl]-1,2,4-diazole-5-base]
The preparation of propionic ester
In the anhydrous DMF of 50mL containing carbonyl dimidazoles (4.5g, 27.6mmol), it is slowly added dropwise
30mL anhydrous DMF solution containing 3-(ethoxy carbonyl) propanoic acid (4.4g, 30mmol), stirs under room temperature
1h, be slowly added in solution (E)-N-hydroxyl-4-[2-(trifluoromethoxy) phenyl] piperidines-1-carbonamidine (7.0g,
23.0mmol), 5h is stirred in reaction at 110 DEG C, and after cooling, decompression is distilled off solvent.Residue silica gel column chromatography (oil
Ether/ethyl acetate=1/1) ethyl-3-[3-[4-[2-(trifluoromethoxy) phenyl] piperidin-1-yl]-1,2,4-diazole-
5-yl] propionic ester 6.8g (yield: 71%).
1H-NMR(400MHz,CDCl3): δ 7.14-7.05 (m, 2H), 6.63-6.51 (m, 2H), 4.13 (q, J=7.2Hz,
2H), 3.51 (d, J=12.0Hz, 2H), 3.17 (t, J=7.6Hz, 2H), 3.12-3.04 (m, 2H), 2.72-2.70 (m, 1H),
2.61 (t, J=7.6Hz, 2H), 1.98-1.64 (m, 4H), 1.25 (t, J=7.2Hz, 3H)；LC/MS(M+1)+=414.2.
4th step: 3-[3-[4-[2-(trifluoromethoxy) phenyl] piperidin-1-yl]-1,2,4-diazole-5-base] propanoic acid
Preparation
By ethyl-3-[3-[4-[2-(trifluoromethoxy) phenyl] piperidin-1-yl]-1,2,4-diazole-5-base] propanoic acid
Ester (6.5g, 15.7mmol) adds in 60mL ethanol/water (1:1), adds sodium hydroxide (1.9g, 47.1mmol) in solution,
Being stirred at room temperature 12h, decompression removes ethanol, with 1N HCl, solution ph is adjusted to 5.0, and ethyl acetate extracts, and separates organic
Phase, aqueous salt solu-tion, it is dried organic facies, is concentrated under reduced pressure to give 3-[3-[4-[2-(trifluoromethoxy) phenyl] piperidines-1-
Base]-1,2,4-diazole-5-base] propanoic acid 5.6g (yield: 93%).LC/MS(M)+=385.1.
5th step: N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-[2-(trifluoromethoxy) phenyl] piperazine
Pyridine-1-base]-1,2,4-diazole-5-base] preparation of propionic acid amide.
By 3-[3-[4-[2-(trifluoromethoxy) phenyl] piperidin-1-yl]-1,2,4-diazole-5-bases] propanoic acid (5.2g,
13.5mmol) join in 60mL dichloromethane, in solution, add 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine
Hydrochlorate (EDCI, 2.9g, 15.0mmol), I-hydroxybenzotriazole (HOBt, 2.0g, 15.0mmol), triethylamine (3.5g,
34.0mmol), 30min is stirred at room temperature, in reactant liquor add N-Methylimidazole. [1,2-a] piperazine-6-amine (2.2g,
15.0mmol), reaction is stirred at room temperature overnight, stopped reaction, and dichloromethane uses water mutually, and saturated aqueous common salt washs, and collection has
Machine phase, anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure obtains crude product, crude product silica gel column chromatography (petrol ether/ethyl acetate=1/
1) N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-[2-(trifluoromethoxy) phenyl] piperidin-1-yl]-1,
2,4-diazole-5-base] propionic acid amide. 5.6g (yield: 81%).
1H-NMR(400MHz,CDCl3):δ8.62(s,1H),8.31(s,1H),7.26-7.05(m,4H),6.63-6.50
(m, 2H), 3.51 (d, J=12.0Hz, 2H), 3.17 (t, J=7.6Hz, 2H), 3.12-3.04 (m, 2H), 2.72-2.70 (m,
1H), 2.71 (s, 3H), 2.61 (t, J=7.6Hz, 2H), 1.98-1.85 (m, 2H), 1.80-1.76 (m, 2H)；LC/MS(M+1
)+=516.2.
The compound of formula I meeting claims all can use the synthetic method with above-described embodiment approximation to obtain, only
Different starting materials need to be changed.Representational compound is as follows:
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-[2-(trifluoromethoxy) phenyl] piperidines-1-
Base]-1,2,4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-[4-(trifluoromethoxy) phenyl] piperidines-1-
Base]-1,2,4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-[2,4-bis-(trifluoromethoxy) phenyl] piperidines-
1-yl]-1,2,4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-[2-(methoxyl group) phenyl] piperidin-1-yl]-1,
2,4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-[4-(methoxyl group) phenyl] piperidin-1-yl]-1,
2,4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-[2,4-bis-(methoxyl group) phenyl] piperidines-1-
Base]-1,2,4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(2-aminomethyl phenyl) piperidin-1-yl]-1,2,4-
Diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(4-aminomethyl phenyl) piperidin-1-yl]-1,2,4-
Diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(2,4-3,5-dimethylphenyl) piperidin-1-yl]-1,
2,4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(2-chlorphenyl) piperidin-1-yl]-1,2,4-
Diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(4-chlorphenyl) piperidin-1-yl]-1,2,4-
Diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(2,4 dichloro benzene base) piperidin-1-yl]-1,2,
4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(2-fluorophenyl) piperidin-1-yl]-1,2,4-
Diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(4-fluorophenyl) piperidin-1-yl]-1,2,4-
Diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-N-methyl-3-[3-[4-(2,4 difluorobenzene base) piperidin-1-yl]-1,2,
4-diazole-5-base] propionic acid amide.；
N-[imidazoles (1,2-a) piperazine-6 base]-3-[3-[4-(2-pyridine radicals) piperidin-1-yl]-1,2,4-diazole-5-
Base] propionic acid amide..Determination of activity
Carry out tests below to determine the activity of formula (I) compound.
Radioligand combines and measures
The compounds of this invention uses expression people CNR1 or the CNR2 receptor of suggestion amount to the affinity of cannabinoid CB 1 receptor
The membrane product (PerkinElmer) of human embryo kidney (HEK) cell each respectively in connection with 1.5 or 2.6nM [3H]-CP-55,940
(Perkin Elmer) determines as radioligand.Be combined in combination buffer that cumulative volume is 0.2ml (for CB1 receptor:
50mM Tris, 5mMMgCl2,2.5mM EDTA, and 0.5% (wt/vol) FAF BSA, PH7.4, and for CB2 receptor:
50mM Tris, 5mM MgCl2,2.5mM EGTA, and 0.1% (wt/vol) FAF BSA, pH 7.4) in carry out, 30
DEG C concussion 1h.By coated micro-filtration plate (the UniFilter GF/B screen plate having 0.5% polymine；Packard)
Fast filtering is by reaction terminating.Nonlinear regression analysis (Activity Base, ID Business is used for Ki
Solution, Limited) analyze the radioactivity of combination, for [3H] CP55, the Kd value of 940 determines from saturation testing.Formula
(I) compound shows the excellent affinity for CB2 receptor, and affinity is less than 20 μMs.
The compound according to Formulas I activity (Ki) particularly 1nM to 10 μM in said determination, more particularly 1nM to 2 μ
M。
CAMP measures
The Chinese hamster ovary celI expressing people CB1 or CB2 receptor is seeded in before the experiments for 17-24 hour with 50.000 cells/well
Have in black 96 hole flat board (Corning Costar#3904) of clear flat bottom, at DMEM (Invitrogen No.31331)
In, supplement 1x HT, there is 10% hyclone, and in moistening incubator at 5%CO2 and 37 DEG C incubation 30 minutes.Add
Entering compound to the final volume that measures is 100 μ l, and 30 DEG C of incubations 30 minutes.Use cAMP-Nano-TRF detectable
Box (Roche Diagnostics), by add 50 μ l lytic reagents (Tris, NaCl, 1.5%Triton X100,2.5%
NP40,10%NaN3) and 50 μ l detection solution (20 μMs of mAb Alexa700-cAMP 1:1, and 48 μMs of ruthenium-2-AHA-cAMP)
Terminate measuring, and shaken at room temperature 2h.By being equipped with the ND:YAG laser instrument TRF reader (Evotec as lasing light emitter
Technologies GmbH) measure the transfer of time resolution energy.By plane-table operation twice, excite and respectively 730 at 355nm
(bandwidth 30nm) or 645nm (bandwidth 75nm) with door (gate) transmitting postponed with 100ns of 100ns, total open-assembly time are
10s.FRET signal is calculated as follows: FRET=T730-Alexa730-P (T645-B645), P=Ru730-B730/Ru645-
B645, wherein T730 is the instrument connection measured at 730nM, and T645 is the instrument connection measured at 645nM, B730 and B645 is respectively
Buffer control at 730nM and 645nM.CAMP content is from the function that span is from 10 μMs to the standard curve of 0.1nM cAMP
Measure.
Use Activity Base to analyze (ID Business Solution, Limited) and measure EC50 value.From this survey
The EC50 value of the cannabinoid agonists of the wide scope that fixed output quota is raw is coincide with the value disclosed in scientific literature.
All compounds according to the present invention are CB2 agonist, and its EC50 is less than 5uM, particularly lower than 2uM.Such as,
Following compound shows with lower people's EC50 value (expressing with uM) in above-mentioned functions cAMP measures:
Claims (5)
1. compound of formula I, and/or their officinal salt
Wherein, R1For aryl, heteroaryl, R2For H, (C1-C6) straight or branched alkyl.
2. according to the compound of formula I of claim 1, wherein R1Selected from 2-Trifluoromethoxyphen-l, 4-Trifluoromethoxyphen-l, 2,
4-bis-Trifluoromethoxyphen-l, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-Dimethoxyphenyl, 2,4-3,5-dimethylphenyl,
2-fluorophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 2-chlorphenyl, 4-chlorphenyl, 2,4 dichloro benzene base, 2-pyridine radicals；R simultaneously2
Selected from H, methyl.
3. in claim 1 and 2 at least one compound of formula I described in any one and/or its officinal salt for prevention and/
Or it is treatment pain, inflammation, inflammatory bowel, glaucoma, diabetes, diabetic retinopathy, atherosclerosis, senile
Macular degeneration disease, acute hepatic failure, hepatic fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosing, ischemia-reperfusion damage
Wound, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerule nephropathy, cardiomyopathy, the heart
Force failure, myocardial ischemia, myocardial infarction, systemic sclerosis, hot injury, burn, hypertrophic scar, gingivitis heating, liver cirrhosis or
Tumor, osteoporosis, neural degeneration, apoplexy.
4. the purposes described in claim 3, inflammation that disease therein refers to, inflammatory bowel, glaucoma, diabetes, nephropathy, the heart
Myopathy.
5. medicine, its comprise in the claim 1 and 2 of effective dose at least one compound of formula I described in any one and/or its
Officinal salt, the excipient of physiology's tolerance and carrier, and also have other additives and/or other activity to become in due course
Point.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610689120.6A CN106317059B (en) | 2016-08-19 | 2016-08-19 | A kind of 2 (CB2) agonist of Cannabined receptor |
Applications Claiming Priority (1)
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| WO2019025474A1 (en) * | 2017-08-02 | 2019-02-07 | Centro Cardiologico Monzino S.p.A. | Modulation of endocannabinoid system and uses thereof in the context of induced pluripotent stem cell-based applications and therapy for cardiomyopathies |
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| WO2007096764A2 (en) * | 2006-02-27 | 2007-08-30 | Glenmark Pharmaceuticals S.A. | Bicyclic heteroaryl derivatives as cannabinoid receptor modulators |
| WO2008141239A1 (en) * | 2007-05-10 | 2008-11-20 | Acadia Pharmaceuticals Inc. | Imidazol [1,2-a] pyridines and related compounds with activity at cannabinoid cb2 receptors |
| CN105189493A (en) * | 2013-02-27 | 2015-12-23 | 持田制药株式会社 | Novel pyrazole derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007096764A2 (en) * | 2006-02-27 | 2007-08-30 | Glenmark Pharmaceuticals S.A. | Bicyclic heteroaryl derivatives as cannabinoid receptor modulators |
| WO2008141239A1 (en) * | 2007-05-10 | 2008-11-20 | Acadia Pharmaceuticals Inc. | Imidazol [1,2-a] pyridines and related compounds with activity at cannabinoid cb2 receptors |
| CN105189493A (en) * | 2013-02-27 | 2015-12-23 | 持田制药株式会社 | Novel pyrazole derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019025474A1 (en) * | 2017-08-02 | 2019-02-07 | Centro Cardiologico Monzino S.p.A. | Modulation of endocannabinoid system and uses thereof in the context of induced pluripotent stem cell-based applications and therapy for cardiomyopathies |
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