CN108586294A - A kind of carbamide derivative and its application in preventing inflammation - Google Patents
A kind of carbamide derivative and its application in preventing inflammation Download PDFInfo
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- CN108586294A CN108586294A CN201810532967.2A CN201810532967A CN108586294A CN 108586294 A CN108586294 A CN 108586294A CN 201810532967 A CN201810532967 A CN 201810532967A CN 108586294 A CN108586294 A CN 108586294A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/64—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups singly-bound to oxygen atoms
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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
A kind of application the invention discloses carbamide derivative and its in preventing inflammation,Wherein：R1、R2、R3It is independently selected from H, F or NO2.From active determination in vitro result, the compounds of this invention has 5 lipoxygenase inhibitory activities and Prostaglandin E Synthase inhibitory activity, more deeply extensive research can be carried out as the drug for the treatment of inflammation, the inflammation can be gynaecology's class inflammation, hepatitis, myocarditis, encephalitis, ephritis, pneumonia, tracheitis, pharyngitis, periodontitis, gastritis, enteritis etc..
Description
Technical field
The invention belongs to chemical medicines, are related to a kind of carbamide derivative and its application in preventing inflammation.
Background technology
Inflammation (inflammation) refers to that the defence that there is the living tissue of vascular system damage factor to be occurred is anti-
It answers.Vascular reaction is the key link of inflammatory process.Inflammation is exactly " inflammation " usually described in people, is body for stimulation
A kind of defense reaction, show as red, swollen, hot, pain and dysfunction.Inflammation can be infective inflammation caused by infection,
It can not be the non-infectious inflammation caused by infection.Under normal conditions, inflammation is beneficial, is the automatic defence of human body
Reaction, but sometimes, inflammation is also harmful, for example, to the attack of human body autologous tissue, be happened at the inflammation of hyaline tissue
Disease etc..In inflammatory process, one side damage factor is caused directly or indirectly the destruction of tissue and cell, on the other hand passes through
Inflammatory congestion and exudation are reacted, and with dilution, killing and surround damage factor.Simultaneously by the regeneration of essence and interstitial cell make by
The tissue of damage is able to repair and heal.It can be said that inflammation is the unified process of damage and antibody Monoclonal.
5- lipoxygenase (5-lipoxygenase enzyme, 5-LOX) is that metabolism arachidonic acid generation inflammatory mediator is white
The key enzyme of trienes compound.The adjusting of 5-LOX has important role to the occurrence and development of inflammation related disease, the enzyme quilt
It is considered one of the important target of anti-inflammatory drug design.Zileuton (zileuton) is only at present into clinical research and conduct
The 5-LOX inhibitor that prescription medicine uses, for treating the relevant disease of asthma.
Prostaglandin E Synthase (Microsomal prostaglandin E-2synthase-1, mPGES-1) is metabolism
Arachidonic acid generates the key enzyme of inflammatory mediator prostanoid.MPGES-1 was found in 1999, before it is located at
Row parathyrine class inflammatory mediator generates the least significant end of access, and the ability up-regulated expression amount only under inflammation-induced, mPGES-1 is considered as can
The anti-inflammatory drugs target of toxic side effect is avoided, there is presently no mPGES-1 inhibitor to enter clinical test.
Invention content
The invention discloses a kind of carbamide derivative, general structure is formula I
Wherein：R1、R2、R3It is independently selected from H, F or NO2.The invention further relates to described
The pharmaceutically acceptable salt or solvate of Formula I.
Further, Formula I described in some preferred schemes is
The synthetic route that another object of the present invention discloses the Formula I is：
The specific synthetic method of 1- hydroxyls -1- (2- (3- nitrobenzophenones) -2,3- dihydro -1H- indenes -1- bases) urea is：It is closed
At steps are as follows：
1) in a suitable solvent, to bromo- 2, the 3- dihydros -1H- indenes -1- alcohol of 2-, triethylamine DCM solution in methane is added dropwise
Sulfonic acid chloride stirs 2 hours, and water stratification, separating and extracting is added to wash, after dry organic phase, solvent is removed in vacuum after being warmed to room temperature,
The bromo- 2,3- dihydros -1H- indenes -1- base methanesulfonic acids of 2- of grease can be obtained；
2) using dichloromethane as solvent, in the grease obtained one step up, 50% hydroxylamine hydrochloride and triethylamine is added,
Reflux, is quenched with water reaction, N- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) azanol can be obtained through subsequent processing；
3) N- obtained in the previous step (the bromo- 2,3- dihydros -1H- indenes -1- bases of 2-) azanol is handled with KOCN and concentrated hydrochloric acid
To 1- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamides；
4) with H2O:EtOH(1:1) it is solvent, PdNPs (0.4mmol%Pd) is catalyst, the 1- (2- forwardly obtained
Bromo- 2,3- dihydros -1H- indenes -1- bases) corresponding boric acid and inorganic base is added in -1- hydroxycarbamides, in a nitrogen atmosphere by mixture
It is vigorously stirred in 60 DEG C 10 minutes, final solid product is obtained through subsequent processing.
Further, the solvent in the step 1) can be dichloromethane, dichloroethanes, pentane, n-hexane etc., excellent
Select dichloromethane.
Further, return time is 1.5 hours to 4 hours, preferably 2 hours in the step 2).
Further, the inorganic base in the step 4) can be potassium carbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate etc. is excellent
Select potassium carbonate.
Another object of the present invention provides the Formula I and is used as 5- lipoxidase inhibitors and/or prostate
The application of plain E synthetase inhibitors.
Another object of the present invention provides the Formula I in preventing or treating inflammation related disease drug
Using.
Further, the inflammation is selected from gynaecology's class inflammation, hepatitis, myocarditis, encephalitis, ephritis, pneumonia, tracheitis, pharynx
Inflammation, periodontitis, gastritis, enteritis etc..
Pharmaceutically acceptable salt of the present invention refers to the organic salt and inorganic salts of the compounds of this invention.Pharmaceutically may be used
The acid-addition salts of receiving can be formed with inorganic acid and organic acid, including but not limited to, acetate, aspartate, benzene first
Hydrochlorate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate
(camphorsulfornate), chloride/hydrochloride, chloro theophylline salt (chlortheophyllonate), citrate, second two
Sulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, hydroxyl second
Base sulfonate, lactate, Lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate,
Mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, octadecane hydrochlorate, oleate, oxalates,
Palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, Polygalacturonate, propionate, stearic acid
Salt, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetate.Can the nothing of salt be obtained by its derivative
Machine acid includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.The organic acid that salt can be obtained by its derivative includes such as second
Acid, propionic acid, glycolic, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid,
Methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid etc..
Solvate of the present invention refers to that one or more solvent molecules are formed by with the compound of the present invention and form
Close object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate,
Acetic acid and ethylaminoethanol.
Specific embodiment
Embodiment 1：The synthesis of 1- hydroxyls -1- (2- (3- nitrobenzophenones) -2,3- dihydro -1H- indenes -1- bases) urea
The synthesis of the bromo- 2,3- dihydros -1H- indenes -1- base methanesulfonic acids of 1-1,2-：
To bromo- 2, the 3- dihydros -1H- indenes -1- alcohol (10.0g, 46.93mmol) of 0 DEG C of 2-, triethylamine (10.8g,
Methane sulfonyl chloride MsCl (9.9g, 86.43mmol) is added dropwise in DCM (50mL) solution 106.73mmol), in 30 minutes
It drips.Mixture is stirred for 2 hours, room temperature is then heated to.Water (50mL) is added, detaches DCM layers, water phase uses DCM again
It is extracted twice (2 × 30mL).Combined organic phase is washed with brine (50mL), then uses Na2SO4It is dry.It removes under vacuum
Solvent obtains bromo- 2, the 3- dihydros -1H- indenes -1- base methanesulfonic acids of light grease 2-, and yield 13.53g, yield 99%, the product is not
It is directly used in through being further purified in next step.1H-NMR(400MHz,CDCl3)δ:3.16(s,3H),3.27(d,1H),3.56
(d,1H),5.66(t,1H),5.92(d,1H),7.02-7.28(m,4H).13C-NMR(125MHz,CDCl3)δ:39.54,
40.62,54.46,87.41,124.93,125.21,126.28,128.57,140.16,144.26.LC-MS(ESI,pos,
ion)m/z:292[M+H].
The synthesis of 1-2, N- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 2-) azanol：
After being dried 30 minutes on vacuum pump, the grease (13.53g, 46.47mmol) that synthesis step 1-1 is obtained is molten
In 30mL dichloromethane.Into the solution be added 50% hydroxylamine hydrochloride (9.5g, 136.71mmol) and triethylamine (7.8g,
77.08mmol).The reaction mixture is flowed back 2 hours, is quenched with water, is extracted with dichloromethane.Organic layer is molten with saturation NaCl
Liquid washs, with anhydrous MgSO4Dry, vacuum evaporation obtains grease, by flash column chromatography (silica, 1:1 hexane/second
Acetoacetic ester) purifying.N- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) azanol is obtained, yield 10.07g, yield is 95%.1H-NMR
(400MHz,CDCl3)δ:1.96(s,1H),2.02(s,1H),3.23-3.42(m,2H),4.45(d,1H),5.45(q,1H),
7.02-7.28(m,4H).13C-NMR(125MHz,CDCl3)δ:38.87,50.04,74.66,124.31,126.29,126.39,
126.91,142.72,143.09.LC-MS(ESI,pos,ion)m/z:229[M+H].
The synthesis of 1-3,1- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamides：
N- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) azanol (10.07g, 44.15mmol) that synthesis step 1-2 is obtained
It is mixed with KOCN (4.77g, 52.98mmol), is cooled to about 5 DEG C, concentrated hydrochloric acid (31.5%HCl aqueous solutions) is then added, with shape
Resulting mixture 1- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamides.Temperature control is between 5-30 DEG C during this.It adds dense
After hydrochloric acid, the temperature of mixture 1- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamides is adjusted to about 40 DEG C.And it stirs
About 6 hours.It being extracted with dichloromethane after restoring room temperature, organic phase is washed twice with saturated sodium bicarbonate solution, after concentrated solvent,
Flash column chromatography detaches, and obtains yellow 1- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamide powder 10.77g, yield
90%.1H-NMR(400MHz,CDCl3)δ:3.27(dd,1H),3.76(dd,1H),5.19(q,1H),5.42(d,1H),5.45
(s,2H),7.06(t,1H),7.13(t,1H),7.22(t,1H),7.26(t,1H),7.82(s,1H).13C-NMR(125MHz,
CDCl3)δ:39.64,50.72,70.12,124.88,126.31,127.28,127.52,142.54,142.78,
164.77.LC-MS(ESI,pos,ion)m/z:272[M+H].
The synthesis of 1-4,1- hydroxyl -1- (2- (3- nitrobenzophenones) -2,3- dihydro -1H- indenes -1- bases) urea：
Synthesis step 1-3 is obtained 1- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamides (10.77g,
39.73mmol) it is dissolved in the H of 96mL2O:EtOH(1:1) it is placed in mixture in three-necked bottle (250mL).By (3- nitrobenzenes
Base) boric acid (9.26g, 55.47mmol) and potassium carbonate (8.29g, 59.99mmol) is added in the mixture.Then it is added
PdNPs catalyst (0.4mmol%Pd), and mixture is vigorously stirred 10 minutes in a nitrogen atmosphere in 60 DEG C.Reaction is mixed
Object is closed to be added in 0.2mol/L sodium hydroxide solutions (55mL) and extracted with ethyl acetate (40mL).Organic layer is merged, and
It volatilizees and crystallizes in air, obtain solid product 1- hydroxyls -1- (2- (3- nitrobenzophenones) -2,3- dihydro -1H- indenes -1- bases) urea,
11.20g, yield 90%.1H-NMR(400MHz,CDCl3)δ:3.11(s,1H),3.41-3.51(m,2H),3.69(q,
1H),5.32(s,2H),5.39(d,1H),7.06(t,1H),7.13(t,1H),7.22(t,1H),7.26(t,1H),7.61(t,
1H),7.67(t,1H),8.09(d,1H),8.26(s,1H).13C-NMR(125MHz,CDCl3)δ:40.49,52.70,68.63,
119.59,123.79,124.88,126.16,127.26,128.40,128.61,134.29,141.45,143.62,145.57,
148.22,164.77.LC-MS(ESI,pos,ion)m/z:314[M+H]。
Embodiment 2：The synthesis of 1- hydroxyls -1- (2- (3- fluoro-phenyls) -2,3- dihydro -1H- indenes -1- bases) urea：
1- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamides (10.77g, 39.73mmol) are dissolved in 96mL's
H2O:EtOH(1:1) it is placed in mixture in three-necked bottle (250mL).By the fluoro- phenyl boric acids of 3- (55.47mmol) and potassium carbonate
(8.29g, 59.99mmol) is added in the mixture.Then PdNPs catalyst (0.4mmol%Pd) is added, and by mixture
It is vigorously stirred in a nitrogen atmosphere in 60 DEG C 10 minutes.Reaction mixture is added to 0.2mol/L sodium hydroxide solutions (55mL)
In and with ethyl acetate (40mL) extract.Organic layer is merged, and volatilizees and crystallizes in air, obtains solid product 1- hydroxyls -1-
(2- (3- fluoro-phenyls) -2,3- dihydro -1H- indenes -1- bases) urea, 10.45g, yield 92%.LC-MS(ESI,pos,ion)m/
z:287[M+H]。
Embodiment 3：The synthesis of 1- hydroxyls -1- (2- phenyl -2,3- dihydro -1H- indenes -1- bases) urea：
1- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamides (10.77g, 39.73mmol) are dissolved in 96mL's
H2O:EtOH(1:1) it is placed in mixture in three-necked bottle (250mL).By phenyl boric acid (55.47mmol) and potassium carbonate
(8.29g, 59.99mmol) is added in the mixture.Then PdNPs catalyst (0.4mmol%Pd) is added, and by mixture
It is vigorously stirred in a nitrogen atmosphere in 60 DEG C 10 minutes.Reaction mixture is added to 0.2mol/L sodium hydroxide solutions (55mL)
In and with ethyl acetate (40mL) extract.Organic layer is merged, and volatilizees and crystallizes in air, obtains solid product 1- hydroxyls -1-
(2- phenyl -2,3- dihydro -1H- indenes -1- bases) urea, 9.05g, yield 85%.LC-MS(ESI,pos,ion)m/z:269[M+
H]。
Embodiment 4：The synthesis of 1- hydroxyls -1- (2- (3,5- difluorophenyls) -2,3- dihydro -1H- indenes -1- bases) urea：
1- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 2-) -1- hydroxycarbamides (10.77g, 39.73mmol) are dissolved in 96mL's
H2O:EtOH(1:1) it is placed in mixture in three-necked bottle (250mL).By bis- fluoro- phenyl boric acids (55.47mmol) of 3,5- and carbon
Sour potassium (59.99mmol) is added in the mixture.Then PdNPs catalyst (0.4mmol%Pd) is added, and mixture is existed
It is vigorously stirred 10 minutes in 60 DEG C under nitrogen atmosphere.Reaction mixture is added in 0.2mol/L sodium hydroxide solutions (55mL)
It is used in combination ethyl acetate (40mL) to extract.Organic layer is merged, and volatilizees and crystallizes in air, obtains solid product 1- hydroxyl -1- (2-
(3,5- difluorophenyl) -2,3- dihydro -1H- indenes -1- bases) urea, 10.99g, yield 91%.LC-MS(ESI,pos,ion)m/
z:305[M+H]。
Test example：The compounds of this invention is active determination in vitro
The small molecule compound of carbamide derivative of the present invention is using fluorescence spectrophotometry 5-LOX's
External activity, using the external activity of enzyme-linked immunosorbent assay mPGES-1, positive control zileuton and MF63 are respectively
The inhibitor of 5- lipoxygenase, the inhibitor of Prostaglandin E Synthase.It is described below：
One, the external activity of fluorescence spectrophotometry 5-LOX
The survey of fluorescence spectrophotometry principle living is that the reaction intermediate 5-HPETE based on 5-LOX can show fluorescence
Toner H2DCFDA oxidations generate the molecule DCF, excitation wavelength 500nm, launch wavelength 520nm of high fluorescence activity.It surveys and lives
When, first 5-LOX enzymes are added and survey buffer solution (50mM Tris-HCl, pH 7.5,0.2mMATP, 0.1mM living
Dithiothreitol (dithiothreitol (DTT), DTT), 0.1mM EDTA, 0.5mM CaCl2) in, 25 DEG C of incubations in 96 orifice plates
10min is balanced.Color developing agent H is added2(final concentration of 25 μM) startings of DCFDA (final concentration of 10 μM) and Cytochrome P450 Arachidonic Acid Epoxygenase substrate
Reaction is used in combination the production quantity of fluorescence microplate reader monitoring fluorescence-causing substance DCF to change with time (excitation wavelength 500nm, transmitted wave
A length of 520nm).Experiment uses method of initial rate, fluorescence intensity change rate when being reacted less than 10% fluorescent color-developing agent as
The initial rate of reaction.All experiments are completed at 25 DEG C, and live body system is 220 μ l.
When measuring inhibiting effect of the micromolecular compound to enzyme, small molecule needs to be dissolved with DMSO, and wants elder generation and enzyme
One arises from and adds substrate starting reaction after 25 DEG C of preincubate 10min.When containing DMSO in system, the final concentration (v/ of DMSO
V) it is generally 5%, no more than 10%, otherwise enzyme can be caused to inactivate.Substrate A A's is a concentration of when measuring the inhibiting rate of small molecule
25μM。
Two, the external activity of enzyme-linked immunosorbent assay mPGES-1
The enzymatic activity of mPGES-1 is characterized by quantitative determining the PGE2 that mPGES-1 catalysis substrate PGH2 conversions generate
's.The PGE2 amounts that catalysis generates are measured using PGE2 enzyme-linked immunosorbent assay kits (Cayman).Assay method is referring to reagent
Box specification.When surveying living, first substrate PGH2 is added in 96 orifice plates of 4 DEG C of constant temperature.100 μ l enzyme initiation reactions are added.4 DEG C anti-
After answering 1min, 150 μ l terminate liquids (50mM FeCl are added2With 100mM citric acids) terminate reaction.Solution uses after dilution
PGE2 enzyme-linked immunosorbent assay kits measure the content of product PGE2.It should be noted that unstable constant volume under substrate PGH2 high temperature
It easily decomposes, when use will be placed in always in 4 DEG C of isoperibols.
When measuring inhibiting effect of the micromolecular compound to enzyme, small molecule needs to be dissolved with DMSO, and wants elder generation and enzyme
One arises to be then added to after 4 DEG C of preincubate 15min in substrate and originates reaction.When containing DMSO in system, the final concentration of DMSO
(v/v) it is generally 2%, no more than 10%, otherwise enzyme can be caused to inactivate.Substrate PGH2's is dense when measuring the inhibiting rate of small molecule
Degree is 17 μM.
Three, external activity result
By active determination in vitro result it is found that the compounds of this invention has 5- lipoxygenase inhibitory activities and prostaglandin E
Enzyme inhibition activity is synthesized, can carry out more going deep into extensive research as the drug for the treatment of inflammation, the inflammation can be
Gynaecology's class inflammation, hepatitis, myocarditis, encephalitis, ephritis, pneumonia, tracheitis, pharyngitis, periodontitis, gastritis, enteritis etc..
Claims (7)
1. a kind of carbamide derivative, general structure is formula I,
Wherein：R1、R2、R3It is independently selected from H, F or NO2。
2. the pharmaceutically acceptable salt or solvate of Formula I as described in claim 1.
3. Formula I as described in claim 1, characterized in that be selected from following compound：
4. the synthetic route of Formula I as described in claim 1 is：
5. Formula I as claimed in claim 1 or 2 presses down as 5- lipoxidase inhibitors and/or Prostaglandin E Synthase
The application of preparation.
6. application of the Formula I as claimed in claim 1 or 2 in preventing or treating inflammation related disease drug.
7. inflammation as claimed in claim 6, selected from gynaecology's class inflammation, hepatitis, myocarditis, encephalitis, ephritis, pneumonia, tracheitis,
Pharyngitis, periodontitis, gastritis, enteritis etc..
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