CN107880024A - A kind of cannabinoid receptor agonists and its synthetic method for being used to treat inflammation - Google Patents
A kind of cannabinoid receptor agonists and its synthetic method for being used to treat inflammation Download PDFInfo
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- CN107880024A CN107880024A CN201711303655.6A CN201711303655A CN107880024A CN 107880024 A CN107880024 A CN 107880024A CN 201711303655 A CN201711303655 A CN 201711303655A CN 107880024 A CN107880024 A CN 107880024A
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- nicotinate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses it is a kind of be used for treat inflammation cannabinoid receptor agonists 4 (4 ((1HThe base of 1,2,3 triazole 1) methyl) 1 naphthalenecarboxamide) methyl nicotinate and its synthesis technique.Compound 4 provided by the invention (4 ((1HThe base of 1,2,3 triazole 1) methyl) 1 naphthalenecarboxamide) methyl nicotinate has good Cannabined receptor Activation Activity, while provide it is a kind of easy to operate, can with it is fairly large prepare cannabinoid receptor agonists 4 (4 ((1HThe base of 1,2,3 triazole 1) methyl) 1 naphthalenecarboxamide) and methyl nicotinate synthesis technique, provide enough 4 for follow-up pharmacy test (4 ((1HThe base of 1,2,3 triazole 1) methyl) 1 naphthalenecarboxamide) methyl nicotinate.
Description
Technical field
Field of the present invention belongs to pharmaceutical synthesis field, and in particular to a kind of cannabinoid receptor agonists for being used to treat inflammation
4-(4-((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) methyl nicotinate and its synthesis technique.
Background technology
Cannabined receptor（Cannabinoid receptors）Be in g protein coupled receptor superfamily a kind of cell membrane by
Body, positioned at whole body, belonging to a part for Endogenous cannabinoid system, it is related to various physiology courses, including appetite, pain,
Mood and memory.As common g protein coupled receptor, Cannabined receptor contains seven cross-film membrane spaning domains.Hemp
Plain acceptor is by three kinds of main ligand activations：The endocannabinoids as caused by mammalian body;Plant cannabinoids（As hemp is planted
The cannabidiol of thing production）With synthesis cannboid（Such as HU-210）.All endocannabinoids and plant cannabinoids are all parents
Lipid, such as fat-soluble compound.
After Cannabined receptor receives acceptor, multiple intracellular signal transduction approach are activated.Originally, Cannabined receptor is main
Suppress adenyl cyclase（So as to produce second messenger molecule ring AMP）, and actively impact inward rectifyimg potassium channel（Kir or
IRK）.However, occur more complicated situation in different cell types, and other potassium-channels, calcium channel, protein kinase
A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun etc. are likely to be affected by it.
There are cannabinoid receptor subtype known to two kinds, referred to as CB1 and CB2 at present.CB1 acceptors are mainly in brain（Nervous centralis
System or " CNS "）Middle expression, but also expressed in lung, liver and kidney.The main table in immune system and hematopoietic cell of CB2 acceptors
Reach.Evidence shows new Cannabined receptor be present, i.e., the non-CB1 and non-CB2 expressed in endothelial cell and CNS.CB1 and CB2
The protein sequence of acceptor is about 44%.When only considering the transmembrane region of acceptor, the amino acid between two kinds of receptor subtypes is similar
Property is about 68%.Further, it has been determined that the minor variations of every kind of acceptor.Cannboid and the reversibly three-dimensional selection of Cannabined receptor
Property combine.Subtype-selective cannboid is developed, it there may be the advantages for the treatment of some disease such as obesity in theory.
Research shows, the cardiac muscle cell of people and rodent, CB1 acceptors in coronary artery endothelial cell and inflammatory cell
Activation promotes Activation In Vitro mitrogen-activated protein（MAP）Kinase p 38 and JNK, active oxygen generation, cell death and angiocarpy
Inflammatory reaction.
Important function based on Cannabined receptor in numerous diseases, develop new cannabinoid receptor agonists and treating
Aspect of inflammation has very big medical value.
The content of the invention
Compound 4- provided by the invention (4- ((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) methyl nicotinate
Cannabined receptor can be activated, the potential application with treatment inflammation.In order to further spread out to cannabinoid receptor agonists 4-
(4-((1H- 1,2,3-triazoles -1- bases) methyl) -1- naphthalenecarboxamides) the follow-up pharmacy test of methyl nicotinate, the invention provides
A kind of fairly large preparation 4- of energy (4- ((1H- 1,2,3-triazoles -1- bases) methyl) -1- naphthalenecarboxamides) methyl nicotinate, and
Its purity can meet the requirement of follow-up test.
The present invention using following route synthesize for treat inflammation cannabinoid receptor agonists 4- (4- ((1H-1,2,
3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) methyl nicotinate, the route of the technique is as follows；
。
The synthesis condition of 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2 is：
By 4- aminonicitinic methyl esters 1,4- methyl isophthalic acids-naphthoic acid（1-3 equivalent）, alkali B1（1-5 equivalent）、DMAP（0.1 - 5
Equivalent）With solvent S1（1-20 times of volume）Mixing, is stirred 12-20 hours at 20-80 DEG C；Added into system molten
Agent S2（1-20 times of volume）, stir 2-5 hours, be filtrated to get 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2.
Alkali B1 be selected from triethylamine, diisopropyl ethyl amine, DBU, DABCO orN- methyl morpholine；Preferable alkali B1 is three second
Amine, diisopropyl ethyl amine orN- methyl morpholine.
Solvent S1 is selected from dimethylformamide, dioxane, tetrahydrofuran, acetonitrile or dichloromethane；Preferable solvent S1
It is dimethylformamide, tetrahydrofuran or dichloromethane.
Solvent S2 is selected from water, dichloromethane, ethyl acetate, toluene or normal heptane；Preferable solvent S2 is water, toluene or just
Heptane.
The synthesis condition of 4- (4- bromomethyl -1- naphthalenecarboxamides) methyl nicotinate 3 is：
By 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2, brominated reagent（1-5 equivalent）, benzoyl peroxide（0.1 - 1
Equivalent）With solvent S3（1-20 times of volume）Mixing, is stirred 1-4 hour at 60-120 DEG C；It is cooled to 20-30
DEG C, water is added into system（1-20 times of volume）, liquid separation obtains organic phase；Solvent S4 is added into organic phase（1-20 times
Volume）, stir 1-2 hour, be filtrated to get 4- (4- bromomethyl-1- naphthalenecarboxamides) methyl nicotinate 3.
Brominated reagent is selected fromN- bromo-succinimide, C5H6Br2N2O2 orN- acetbromamide；Preferable brominated reagent is liquid
Bromine, C5H6Br2N2O2 orN- bromo-succinimide, most preferred brominated reagent areN- bromo-succinimide.
Solvent S3 is selected from dimethylformamide, dimethyl acetamide, dichloromethane, chloroform or carbon tetrachloride；It is preferable molten
Agent S3 is dichloromethane, chloroform or carbon tetrachloride.
Solvent S4 is selected from acetonitrile, toluene, tetrahydrofuran, ethyl acetate or normal heptane；Preferable solvent S4 is toluene, acetic acid
Ethyl ester or normal heptane.
4-(4-((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) synthesis condition of methyl nicotinate is：
By 4- (4- bromomethyl -1- naphthalenecarboxamides) methyl nicotinate 3,1,2,3- triazoles（1-5 equivalent）, alkali B2（1-5 equivalent）
With solvent S5（1-20 times of volume）Mixing, is stirred 15-20 hours at 50-100 DEG C；Water is added into system（1 -
20 times of volumes）, stir 1-3 hour, be filtrated to get 4- (4- ((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) cigarette
Sour methyl esters.
Alkali B2 is selected from triethylamine, diisopropyl ethyl amine, potassium carbonate, potassium hydroxide or pyridine；Preferable alkali B2 is carbonic acid
Potassium, potassium hydroxide or pyridine.
Solvent S5 is selected from dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran or ethyl acetate；Preferable solvent S5
It is dichloromethane, dimethylformamide or ethyl acetate；Most preferred solvent S5 is dimethylformamide.
Synthesis condition and method used in the present invention, simple to operate, raw material is inexpensively easily bought, with short production cycle, can be compared with
It is large-scale prepare cannabinoid receptor agonists 4- (4- ((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) nicotinic acid first
Ester, for follow-up pharmacy test provide enough 4- (4- ((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) nicotinic acid
Methyl esters.By 4- aminonicitinic methyl esters 1 and 4- methyl isophthalic acids-naphthoic acid acylation reaction occurs for the present invention, obtain 4- (4- methyl isophthalic acids-
Naphthalenecarboxamide) methyl nicotinate 2.Then, 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2 existsNThe work of-bromo-succinimide
With lower bromination, obtained 4- (4- bromomethyl -1- naphthalenecarboxamides) methyl nicotinates 3 and 1,2,3-triazoles be condensed to yield 4- (4- ((1H-
1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) methyl nicotinate.
Embodiment
With reference to specific embodiment, the invention will be further described：
Embodiment 1
The synthesis condition of 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2 is：
By 4- aminonicitinic methyl esters 1（22 g）, 4- methyl isophthalic acids-naphthoic acid（70 g）, triethylamine（44 g）、DMAP（7 g）With two
Chloromethanes（120 mL）Mixing, is stirred 12-20 hours at 20-80 DEG C；Toluene is added into system（150 mL）, stir
Mix 2-5 hours, be filtrated to get 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2（34 g）.
1H NMR (400 MHz, DMSO-d6) δ = 2.77 (s, 3H), 4.00 (s, 3H), 7.42 (d,
1H), 7.55−7.66 (m, 3H), 7.80 (d, 1H), 8.03−8.14 (m, 1H), 8.49 (dd, 1H), 8.53−
8.6 (m, 1H), 9.42 (dd, 1H), 11.59 (s, 1H) ppm; m/z (MS-ESI): 321.35 [M + 1]+.
The synthesis condition of 4- (4- bromomethyl -1- naphthalenecarboxamides) methyl nicotinate 3 is：
By 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2（26 g）、N- bromo-succinimide（22 g）, benzoyl peroxide first
Acyl（10 g）And chloroform（60 mL）Mixing, is stirred 1-4 hour at 60-120 DEG C；20-30 DEG C are cooled to, Xiang Ti
Water is added in system（100 mL）, liquid separation obtains organic phase；Toluene is added into organic phase（320 mL）, stir 1-2 hour, mistake
Filter obtains 4- (4- bromomethyl -1- naphthalenecarboxamides) methyl nicotinate 3.
HPLC purity 99%（Retention time: 10.7 min.）;1H NMR (400 MHz, DMSO-d6) δ = 3.85
(s, 3H), 6.22 (s, 2H), 7.45 (d, 1H), 7.64−7.75 (m, 3H), 7.79 (s, 1H), 7.82
(d, 1H), 8.22 (s, 1H), 8.33 (dd, 1H), 8.39 (dd, 1H), 8.46−8.54 (m, 2H), 11.12
(s, 1H) ppm; m/z (MS-ESI): 400.42 [M + 1]+.
4-(4-((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) synthesis condition of methyl nicotinate is：
By 4- (4- bromomethyl -1- naphthalenecarboxamides) methyl nicotinate 3（22 g）, 1,2,3- triazoles（6 g）, pyridine（9 g）And diformazan
Base formamide（90 mL）Mixing, is stirred 15-20 hours at 50-100 DEG C；Water is added into system（180 mL）, stir
Mix 1-3 hour, be filtrated to get 4- (4- ((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenecarboxamides) methyl nicotinate（17 g,
80%）.
HPLC purity 99%（Retention time: 17.1 min.）;1H NMR (400 MHz, DMSO-d6) δ = 3.83
(s, 3H), 6.21 (s, 2H), 7.44 (d, 1H), 7.66−7.74 (m, 3H), 7.77 (s, 1H), 7.85
(d, 1H), 8.23 (s, 1H), 8.32 (dd, 1H), 8.38 (dd, 1H), 8.46−8.52 (m, 2H), 11.06
(s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 165.9, 164.8, 155.0, 151.4, 148.9,
140.5, 133.9, 133.6, 131.8, 131.2, 129.8, 128.9, 126.2, 124.7, 123.1, 120.3,
108.2, 104.7, 53.6, 51.3 ppm; m/z (MS-ESI): 388.21 [M + 1]+.
Bioactivity research
HCB1 and hCB2 receptor binding assays
Using expression cloning hCB2 acceptors rhabdovirus system from the hCB1 acceptors of expression cloning（Clone numbering 24）Or Sf9
The HEK 293S cells of cell produce film.By film in 37 DEG C of defrostings, by No. 23 blunt nosed pins 3 times, and combine and buffer in cannboid
Liquid（50mM Tris, 2.5mM EDTA, 5mM MgCl2BSA aliphatic acid, pH 7.4 are free of with 0.5mg/mL）In, and will contain
80 μ L aliquots of appropriate protein are distributed in 96 orifice plates.Use every hole 20000-25000 dpm（0.17-0.21nM）
's3H-CP55940（70μL）The compounds of this invention is evaluated in 10 μM of dose-effect curve（150μL）At hCB1 and hCB2
IC50Value, final volume is 300 μ L.The absence and presence of 0.2 μM of HU210（150μL）In the case of determine summation it is non-specific
Property combine.
By flat board vortex oscillation, incubate 60 minutes at room temperature, and 3mL lavation buffer solutions are used with Packard croppers
（50mM Tris, 5mM MgCl2, 0.05%BSA, pH7.5）Pass through Unifilters GF/B（It is immersed in 0.1% polyethylene in advance
In imines） pH 7.0）.Filter is dried 1 hour at 55 DEG C.Calculated and specifically bound with TB-NS（SB）, and various
SB in the presence of part is represented with compareing SB percentage.Use Xlfit4（IDBS, Inc.）Calculate and take in ActivityBase
The values of IC 50 and Hill coefficients of the part of the radioligand of generation specific binding（nH）.In addition.Also pass through ActivityBase
Calculate the compound concentration and dilution factor used.Adding 65 μ L/ hole Microscint 20（Packard Biosciences）
After scintillation solution, in TopCount（Packard）Counted for radioactivity（cpm）.
GTPγ[35S] binding tests
The people CB1 acceptors cloned in the film of HEK293S cells or the people CB2 that is cloned in the film of Sf9 cells are by bulk measurement GTP
γ[35S] combine.By film in 37 DEG C of defrostings, by No. 23 blunt nosed pins 3 times, with GTP γ [35S] combination buffer（50mMN-2-
Hydroxyethyl piperazine-N- ethyl sulfonic acid（Hepes））Dilution, 20mM NaOH, 100mM NaCl, 1mM EDTA, 5mM MgCl2, pH
7.4,0.1%BSA with 15 μM of GDP）.EC of the compound at hCB1 and hCB2 is assessed from 10 dose points-response curve50With
Emax。
The measure carried out in 96 orifice plates is made up of 300 μ L, wherein containing the single buffer solutions of 150 μ L or various concentrations
Compound, 80 μ L and 56 μM of GDP（15 μM of final concentrations）The film of mixing（5 μ g proteins/hole）.Finally, 70 μ L tracers GTP are added
γ[35S]（Dupont/NEN, Mandel Scientific, St-Laurent）（100000-130000dpm/ holes）To start
Reaction.8 holes are used to define basis（Negative control）With reference to 8 holes use 10 μM of Rimonabant in addition, for positive control（Most
It is big to combine）.Then by plate on rail mounted blender hand mix and at room temperature be incubated 1 hour, Unifilters GF/
B（Presoak in deionized water）, use 3mL lavation buffer solutions（50mM Tris, 5mM MgCl2, 50mM NaCl, pH 7.4）With
Packard croppers mix.Filter membrane is dried 1 hour at 55 DEG C, then adds 50 μ L Microscint 20（Packard
Biosciences）Scintillation solution.In TopCount（Packard）Radioactivity on middle counting filter（cpm）.GTP γ will be contained
[35S] and 8 holes of film in GTP γ [35S] the cpm values that combine are average to define basic combination, and will be containing 10 μM
The value in Rimonabant 8 holes it is average with define GTP γ [35S] maximum combined.The GTP observed to each compound concentration
γ[35S] with reference to stimulation be expressed as 10 μM of Rimonabant caused by ceiling effect percentage.By subtracting basic combination
Calculating GTP γ [35S] specific binding.Use Xlfit4（IDBS, Inc.）Carry out curve fitting and EC50Calculate.
The biologically active data of the compounds of this invention measured is as follows：
| hCB1 IC50 (nM) | hCB2 IC50 (nM) | hCB1 EC50 (nM) | hCB1 Emax (%) |
| 0.85 | 110 | 1.3 | 110 |
Claims (9)
1. a kind of synthetic method for being used to treat the cannabinoid receptor agonists of inflammation, it is characterised in that the route of the technique is such as
Under；
。
2. preparation technology as claimed in claim 1, it is characterised in that the synthesis of 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2
Condition is：
4- aminonicitinic methyl esters 1,4- methyl isophthalic acids-naphthoic acid, alkali B1, DMAP and solvent S1 are mixed, stirred at 20-80 DEG C
Mix 12-20 hours；
Solvent S2 is added into system, stirs 2-5 hours, is filtrated to get 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2；
Wherein alkali B1 be selected from triethylamine, diisopropyl ethyl amine, DBU, DABCO orN- methyl morpholine, its dosage and 4- amino cigarettes
The mole dosage ratio of sour methyl esters 1 is 1-5：1；
The dosage of 4- methyl isophthalic acids-naphthoic acid is 1-3 with the mole dosage ratio of 4- aminonicitinic methyl esters 1：1；
DMAP dosage is 0.1-5 with the mole dosage ratio of 4- aminonicitinic methyl esters 1：1；
Solvent S1 is selected from dimethylformamide, dioxane, tetrahydrofuran, acetonitrile or dichloromethane, its dosage and 4- amino cigarettes
The volumetric usage ratio of sour methyl esters 1 is 1-20：1；
Solvent S2 is selected from water, dichloromethane, ethyl acetate, toluene or normal heptane, its dosage and the volume of 4- aminonicitinic methyl esters 1
Amount ratio is 1-20：1.
3. preparation technology as claimed in claim 2, it is characterised in that alkali B1 be triethylamine, diisopropyl ethyl amine orN- methyl
Morpholine.
4. preparation technology as claimed in claim 2, it is characterised in that solvent S1 is dimethylformamide, tetrahydrofuran or dichloro
Methane.
5. preparation technology as claimed in claim 1, it is characterised in that 4- (4- bromomethyl -1- naphthalenecarboxamides) methyl nicotinate 3
Synthesis condition is：
4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2, brominated reagent, benzoyl peroxide and solvent S3 are mixed, in 60-
Stirred 1-4 hour at 120 DEG C；
20-30 DEG C are cooled to, water is added into system, liquid separation obtains organic phase；Solvent S4, stirring 1 are added into organic phase
- 2 hours, it is filtrated to get 4- (4- bromomethyl -1- naphthalenecarboxamides) methyl nicotinate 3；
Wherein brominated reagent is selected fromN- bromo-succinimide, C5H6Br2N2O2 orN- acetbromamide, its dosage and 4- (4- methyl-
1- naphthalenecarboxamides) methyl nicotinate 2 mole dosage ratio be 1-5：1；
The dosage of benzoyl peroxide is 0.1-1 with the mole dosage ratio of 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2：
1；
Solvent S3 is selected from dimethylformamide, dimethyl acetamide, dichloromethane, chloroform or carbon tetrachloride, its dosage and 4- (4-
Methyl isophthalic acid-naphthalenecarboxamide) methyl nicotinate 2 volumetric usage ratio be 1-20：1；
Solvent S4 is selected from acetonitrile, toluene, tetrahydrofuran, ethyl acetate or normal heptane, its dosage and 4- (4- methyl isophthalic acids-naphthalene formyl
Amine) methyl nicotinate 2 volumetric usage ratio be 1-20：1；
The dosage of water is 1-20 with the volumetric usage ratio of 4- (4- methyl isophthalic acids-naphthalenecarboxamide) methyl nicotinate 2：1.
6. preparation technology as claimed in claim 5, it is characterised in that preferable brominated reagent be bromine, C5H6Br2N2O2 orN- bromine
For succimide.
7. preparation technology as claimed in claim 1, it is characterised in that the described Cannabinoid receptor agonistic for being used to treat inflammation
The synthesis condition of agent is：
The described cannabinoid receptor agonists for being used to treat inflammation for 4- (4- ((1H- 1,2,3- triazol-1-yls) methyl) -1-
Naphthalenecarboxamide) methyl nicotinate；
4- (4- bromomethyl-1- naphthalenecarboxamides) methyl nicotinate 3,1,2,3-triazoles, alkali B2 and solvent S5 are mixed, in 50-100
Stirred 15-20 hours at DEG C；
Add water into system, stirring 1- 3 hours, be filtrated to get 4- (4- ((1H- 1,2,3- triazol-1-yls) methyl) -1- naphthalenes
Formamide) methyl nicotinate；
Wherein alkali B2 is selected from its dosage of triethylamine, diisopropyl ethyl amine, potassium carbonate, potassium hydroxide or pyridine and 4- (4- bromine first
Base-1- naphthalenecarboxamides) methyl nicotinate 3 mole dosage ratio be 1-5：1；
The dosage of 1,2,3- triazoles is 1-5 with the mole dosage ratio of 4- (4- bromomethyl-1- naphthalenecarboxamides) methyl nicotinate 3：1；
Solvent S5 is selected from dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran or ethyl acetate, its dosage and 4- (4- bromine first
Base-1- naphthalenecarboxamides) methyl nicotinate 3 volumetric usage ratio be 1-20：1；
The dosage of water is 1-20 with the volumetric usage ratio of 4- (4- bromomethyl-1- naphthalenecarboxamides) methyl nicotinate 3：1.
8. preparation technology as claimed in claim 7, it is characterised in that alkali B2 is potassium carbonate, potassium hydroxide or pyridine.
9. preparation technology as claimed in claim 7, it is characterised in that solvent S5 is dichloromethane, dimethylformamide or acetic acid
Ethyl ester.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101001840A (en) * | 2004-05-25 | 2007-07-18 | 阿斯利康(瑞典)有限公司 | Therapeutic compounds: pyridine as scaffold |
| CN101336238A (en) * | 2005-11-24 | 2008-12-31 | 阿斯利康(瑞典)有限公司 | Novel 3-bicyclocarbonylaminopyridine-2-carboxamides or 3-bicyclocarbonylaminopyrazine-2-carboxamides |
| CN101743223A (en) * | 2007-07-09 | 2010-06-16 | 雅培制药有限公司 | Novel compounds as cannabinoid receptor ligands |
-
2017
- 2017-12-11 CN CN201711303655.6A patent/CN107880024A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101001840A (en) * | 2004-05-25 | 2007-07-18 | 阿斯利康(瑞典)有限公司 | Therapeutic compounds: pyridine as scaffold |
| CN101336238A (en) * | 2005-11-24 | 2008-12-31 | 阿斯利康(瑞典)有限公司 | Novel 3-bicyclocarbonylaminopyridine-2-carboxamides or 3-bicyclocarbonylaminopyrazine-2-carboxamides |
| CN101743223A (en) * | 2007-07-09 | 2010-06-16 | 雅培制药有限公司 | Novel compounds as cannabinoid receptor ligands |
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