CN108530433A - A kind of ester derivative and its application in preventing cardiovascular and cerebrovascular disease - Google Patents
A kind of ester derivative and its application in preventing cardiovascular and cerebrovascular disease Download PDFInfo
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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Abstract
A kind of application the invention discloses ester derivative and its in preventing cardiovascular and cerebrovascular disease,Wherein：R1、R2、R3It is independently selected from H, F or CH3.External LCAT activation experiments illustrate that the compounds of this invention has LCAT activations, internal effect experiment illustrates that the compounds of this invention can improve HDL levels, infers that the compounds of this invention can be used for preventing or treating cranial vascular disease, coronary heart disease, artery sclerosis, arteriography, peripheral vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterol mass formed by blood stasis etc..
Description
Technical field
The invention belongs to chemical medicines, are related to a kind of ester derivative and its answering in preventing cardiovascular and cerebrovascular disease
With.
Background technology
Cardiovascular and cerebrovascular disease (cardiovascular and cerebrovascular diseases, CCVd) is heart
The general designation of blood vessel and cranial vascular disease refers to hyperlipidemia, blood is sticky, caused by atherosclerosis, hypertension etc.
Heart, brain and the body tissue ischemic or hemorrhagic disease that occur.Epidemiological study shows coronary heart disease (Coronary
Heart Disease, CHD) incidence in gradually rising trend, seriously affect population health, it has also become threaten human health
A big killer, more and more people are disabled lethal because of CHD.
Lecithin cholesterol acyltransferase (lecithin-cholesterolacyltransferase, LCAT) by
Liver synthesis is released into blood, exists in the form of dissociating or be combined with lipoprotein, is a kind of enzyme playing catalytic action in blood plasma,
It is that the positions the C2 unsaturated fatty acid of the lecithin of HDL is transferred to free cholesterol that it, which is acted on, generates lysolecithin and courage is solid
Alcohol ester.Almost 70%-80% is cholesteryl ester to plasma cholesterol, is caused by LCAT catalysis generates.LCAT is often incorporated in HDL
Together, very high in HDL granule surface activities and catalytic action, does not almost work to the particle of VLDL and LDL.LCAT is in people
Key player is play in the metabolism of class plasma cholesterol and HDL metabolism, there is weight for cardiovascular and cranial vascular disease prevention
Want meaning.
Invention content
The invention discloses a kind of ester derivative formula I, structure is：
Wherein：R1、R2、R3It is independently selected from H, F or CH3.The present invention also relates to
And the pharmaceutically acceptable salt or solvate of the ester derivative formula I.
Further, ester derivative formula I described in some preferred schemes is
The synthetic route that another object of the present invention discloses the ester derivative formula I is：
Specifically synthetic method is：
1) compound 1 reacts with cyclopentanone and generates 4- (the amyl- 1- alkene -1- bases of ring) -1H- pyrroles under strongly alkaline conditions
Cough up -2- carboxylic acids (compound 2)；
2) compound 2 is at Pd (OH)2/ C is as catalyst, 1:1 THF-MeOH under the action of solvent as hydrogenating
Reaction generates 4- cyclopenta -1H- pyrroles -2- carboxylic acids (compound 3)；
3) esterification occurs under the action of thionyl chloride, ethyl alcohol for the carboxyl in compound 3, generates 4- cyclopenta -1H-
Pyrroles -2- carboxylic acid, ethyl esters (compound 4)；
4) the substitution reaction generation bromo- 4- cyclopenta -1H- pyrroles -2- carboxylics of 5- occur under the action of bromide reagent for compound 4
Acetoacetic ester (compound 5)；
5) under alkaline condition, compound 5 reacts with corresponding boric acid, generates final product.
Further, the highly basic in the step 1) can be alkali metal hydroxide, alkali metal alcoholates or alkali metal
Hydride in a solvent, preferred as alkali alkoxide, most preferably sodium methoxide.
Further, suitable bromide reagent includes elemental bromine, N-bromosuccinimide, tribromide in the step 4)
Pyridine, dibromo hydantoins and corresponding iodo derivative, preferably pyridinium tribromide.
Further, the alkali in the step 5) can be sodium carbonate, potassium carbonate or potassium acetate etc., preferably sodium carbonate.
Another object of the present invention discloses the ester derivative formula I and swashs as lecithin cholesterol acyltransferase
The application of agent living.
Another object of the present invention discloses I answering in the drug for preparing cardiovascular and cerebrovascular disease of the ester derivative formula
With.
Further, the ester derivative formula I for prevent or treat cranial vascular disease (including apoplexy and cerebral infarction),
Coronary heart disease (including heart failure, myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorder and angiogenic restenosis) is moved
Arteries and veins hardening, arteriography, peripheral vascular disease (including diabetic vascular complications), dyslipidemia, low HDL courage
Sterol mass formed by blood stasis, high LDL cholesterol mass formed by blood stasis 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 salt that the nontoxic acid received is formed includes, but is not limited to, inorganic acid salt, such as hydrochloride, hydrobromate, phosphate, sulfuric acid
Salt, perchlorate；Acylate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, the third two
Hydrochlorate；Or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other can pharmaceutically connect
The salt received includes adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate,
Borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second
Sulfonate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate,
Caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, apple
Hydrochlorate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid
Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11
Hydrochlorate, valerate, etc..By including alkali metal, alkaline-earth metal, ammonium and N+ (C1-4 alkane with alkali appropriate salt obtained by the reaction
Base) 4 salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Can with the alkali metal of forming salt or
Alkaline-earth metal includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, season
The amine cation that ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitre
Acidulants, C1-8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
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 4- cyclopenta -5- (4- fluorine thiophene -2- bases) -1H- pyrroles's -2- Ethyl formates
The synthesis of 1-1,4- (the amyl- 1- alkene -1- bases of ring) -1H- pyrroles's -2- carboxylic acids
Reflux condenser and mechanical agitator are equipped in the round-bottomed flask of 250mL, and whole system is purified with nitrogen.
1H- pyrroles -2- carboxylic acids (1.21g, 10.86mmol) are added in flask, MeOH (15.5mL) is then added.It stirs at room temperature
It mixes after ten minutes, cyclopentanone (2.88mL, 32.58mmol) is added.Methanol/sodium methoxide (25%w/ is added portionwise in 10 minutes
W, 15.15mL, 66.25mmol).Then the mixture is flowed back 24 hours.After being cooled to room temperature, water (23.31mL) is added simultaneously
Methanol is removed under reduced pressure.Remaining water phase is acidified to pH=1 with dense HCl (about 7mL).The pale yellow precipitate being collected by filtration
Object is washed with water and is dried in vacuo at 50 DEG C.Obtain required beige solid 4- (the amyl- 1- alkene -1- bases of ring) -1H- pyrroles -2-
Carboxylic acid (compound 2), 1.91g, yield 99%.1H-NMR(400MHz,CDCl3)δ:1.82(m,2H),2.31(m,2H),2.53
(t,2H),5.75(t,1H),7.02(s,1H),7.05(s,1H),9.03(s,1H).13C-NMR(125MHz,CDCl3)δ:
28.64,31.87,32.20,114.52,116.02,123.12,124.28,128.48,141.40,160.97.LC-MS(ESI,
pos,ion)m/z:178[M+H].
The synthesis of 1-2,4- cyclopenta -1H- pyrroles's -2- carboxylic acids
Unsaturated compound 2 (1.91g, 10.75mmol) obtained above is placed under 50psi Hydrogen Vapor Pressures and is hydrogenated
20 hours use 20%Pd (OH)2/ C is as catalyst, 1:1 THF-MeOH is as solvent.After filtration catalytic agent, decompression
Volatile matter is removed, residue is beaten with hexane.Beige solid is collected by filtration, washed with hexane and is dried in vacuo, obtains 4- rings penta
Base -1H- pyrroles -2- carboxylic acids (compound 3), 1.50g, yield 78%.1H-NMR(400MHz,CDCl3)δ:1.66(m,4H),
1.76(m,2H),1.92(m,2H),3.11(m,1H),7.05(s,1H),7.18(s,1H),8.87(s,1H).13C-NMR
(125MHz,CDCl3)δ:26.10,34.25,36.55,117.72,118.97,126.68,128.71,160.97.LC-MS
(ESI,pos,ion)m/z:180[M+H].
The synthesis of 1-3,4- cyclopenta -1H- pyrroles's -2- carboxylic acid, ethyl esters
Reflux condenser and mechanical agitator are equipped in the three-neck flask of 100mL, and whole system is purified with nitrogen.
Compound 3 (1.50g, 8.37mmol) is added in flask and is suspended in ethyl alcohol (13.58mL).Thionyl chloride is added dropwise
(1mL, 0.42mmol) and mixture is flowed back 24 hours.Volatile matter is removed under reduced pressure, residue is beaten with hexane, is washed with hexane
And obtain yellow solid 4- cyclopenta -1H- pyrroles -2- carboxylic acid, ethyl esters (compound 4), 1.53g, yield 88% after being dried in vacuo.1H-NMR(400MHz,CDCl3)δ:1.30(t,3H),1.66(m,4H),1.76(m,2H),1.92(m,2H),3.07(m,1H),
4.25(q,2H),6.88(s,1H),7.09(s,1H),8.81(s,1H).13C-NMR(125MHz,CDCl3)δ:14.68,
26.10,34.25,36.55,61.45,113.56,118.97,125.06,128.71,161.28.LC-MS(ESI,pos,ion)
m/z:208[M+H].
The synthesis of the bromo- 4- cyclopenta -1H- pyrroles -2- carboxylic acid, ethyl esters of 1-4,5-
Compound 4 (1.53g, 7.38mmol) is dissolved in THF (40mL) and CHCl3The in the mixed solvent of (40mL), then
Solution is cooled down in ice bath and pyridinium tribromide (2.95g, 9.23mmol) is added.After being stirred 1 hour at 0 DEG C, pass through TLC
Judge that reaction is completed.Use CHCl3(100mL) dilutes, and uses the NaHSO of 1mol/L successively3(2*25mL) is saturated NaHCO3(2*
25mL) aqueous solution and brine (25mL) washing.Use Na2SO4After drying, solvent is removed under reduced pressure, residue is tied from TBME- hexanes
It is brilliant.After being collected by filtration, after being washed and dried with hexane, the bromo- 4- cyclopenta -1H- pyrroles -2- carboxylic acid second of 5- of 1.45g red is obtained
Ester solid (compound 5).Red solid can be obtained after evaporation mother liquor, it (is used 15% by purified by flash chromatography
The hexane solution of EtOAc is as eluant, eluent), obtain other 0.34g compounds 5, total output 1.79g, yield 85%.1H-
NMR(400MHz,CDCl3)δ:1.30(t,3H),1.66(m,2H),1.67(m,2H),1.76(m,2H),1.93(m,2H),
3.08(m,1H),4.25(q,2H),6.74(s,1H),8.64(s,1H).13C-NMR(125MHz,CDCl3)δ:14.68,
26.10,34.69,40.95,61.45,109.52,119.08,126.51,132.33,161.64.LC-MS(ESI,pos,ion)
m/z:286[M+H].
The synthesis of 1-5,4- cyclopenta -5- (4- fluorine thiophene -2- bases) -1H- pyrroles's -2- Ethyl formates
By (4- fluorine thiophene -2- bases) boric acid (6.26mmol), compound 5 (1.79g, 6.26mmol), Na2CO3(2.00g,
18.78mmol), DME (10.14mL) and H2O (2.50mL) is added in 50mL microwave vials.Bottle N2Degassing 35 minutes, so
After PdCl is added2(dppf)CH2Cl2(0.55g, 0.75mmol) adduct.By microwave irradiation by reaction mixture at 120 DEG C
Heating 1 hour.Obtained mixture is diluted with ethyl acetate and is filtered by diatomite, is then concentrated in vacuo.Pass through quick color
Spectrometry purifies, and uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtains off-white powder 4- cyclopenta -5- (4- fluorine thiophene -
2- yls) -1H- pyrroles's -2- Ethyl formates, 1.44g, yield 75%.1H-NMR(400MHz,CDCl3)δ:1.30(t,3H),1.66
(m,2H),1.68(m,2H),1.76(m,2H),1.93(m,2H),3.39(m,1H),4.25(q,2H),6.85(s,1H),7.06
(d,1H),7.40(d,1H),9.60(s,1H).13C-NMR(125MHz,CDCl3)δ:14.68,26.10,34.69,40.75,
61.45,113.04,118.61,120.05,125.08,128.49,129.53,138.94,161.62,161.64.LC-MS
(ESI,pos,ion)m/z:308[M+H]。
Embodiment 2：The synthesis of 4- cyclopenta -5- (5- fluorine thiophene -2- bases) -1H- pyrroles's -2- Ethyl formates
By (5- fluorine thiophene -2- bases) boric acid (6.26mmol), compound 5 (1.79g, 6.26mmol), Na2CO3(2.00g,
18.78mmol), DME (10.14mL) and H2O (2.50mL) is added in 50mL microwave vials.Bottle N2Degassing 35 minutes, so
After PdCl is added2(dppf)CH2Cl2(0.55g, 0.75mmol) adduct.By microwave irradiation by reaction mixture at 120 DEG C
Heating 1 hour.Obtained mixture is diluted with ethyl acetate and is filtered by diatomite, is then concentrated in vacuo.Pass through quick color
Spectrometry purifies, and uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtains off-white powder 4- cyclopenta -5- (5- fluorine thiophene -
2- yls) -1H- pyrroles's -2- Ethyl formates, 1.50g, yield 78%.LC-MS(ESI,pos,ion)m/z:308[M+H].
Embodiment 3：The synthesis of 4- cyclopenta -5- (5- methylthiophene -2- bases) -1H- pyrroles's -2- Ethyl formates
By (5- methylthiophene -2- bases) boric acid (6.26mmol), compound 5 (1.79g, 6.26mmol), Na2CO3
(2.00g, 18.78mmol), DME (10.14mL) and H2O (2.50mL) is added in 50mL microwave vials.Bottle N2Degassing 35
Minute, PdCl is then added2(dppf)CH2Cl2(0.55g, 0.75mmol) adduct.By microwave irradiation by reaction mixture
It is heated 1 hour at 120 DEG C.Obtained mixture is diluted with ethyl acetate and is filtered by diatomite, is then concentrated in vacuo.Pass through
Purified by flash chromatography uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtains off-white powder 4- cyclopenta -5- (5-
Methylthiophene -2- bases) -1H- pyrroles's -2- Ethyl formates, 1.29g, yield 68%.LC-MS(ESI,pos,ion)m/z:304[M+
H]。
Embodiment 4：The synthesis of 4- cyclopenta -5- (4,5- difluoro thiophene -2- bases) -1H- pyrroles's -2- Ethyl formates
By (4,5- difluoro thiophene -2- bases) boric acid (6.26mmol), compound 5 (1.79g, 6.26mmol), Na2CO3
(2.00g, 18.78mmol), DME (10.14mL) and H2O (2.50mL) is added in 50mL microwave vials.Bottle N2Degassing 35
Minute, PdCl is then added2(dppf)CH2Cl2(0.55g, 0.75mmol) adduct.By microwave irradiation by reaction mixture
It is heated 1 hour at 120 DEG C.Obtained mixture is diluted with ethyl acetate and is filtered by diatomite, is then concentrated in vacuo.Pass through
Purified by flash chromatography uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtain off-white powder 4- cyclopenta -5- (4,
5- difluoro thiophene -2- bases) -1H- pyrroles's -2- Ethyl formates, 1.61g, yield 79%.LC-MS(ESI,pos,ion)m/z:326
[M+H]。
Test example 1：External LCAT activation experiments
One, experimental program
By density gradient centrifugation separation the part (1.125 being made of HDL3 is obtained from the blood plasma of the people of health<Proportion<
1.210/mL).By the part of acquisition to phosphate-buffered saline (pH 7.4) dialysis and as LCAT enzyme source and receptor.
Each testing drug is prepared by being dissolved in dimethyl sulfoxide (DMSO).DTNB (Ellman reagents, ultimate density will be contained：0.5mM), sulfydryl second
Alcohol (ultimate density：12.5mM) and [14C] cholesterol of 0.6% bovine serum albumin(BSA) is added to the phosphoric acid containing 1mg/mLHDL3
Salt-buffered saline (pH 7.4), and the testing drug of various concentration is further added to so that total amount is adjusted to 80 μ L.37
DEG C cultivate the mixture about 16 hours.Then, mixed solution (mixing ratio=3 of hexane and isopropanol are added to:2) to stop
Reaction.After stirring, hexane layer is collected, and evaporates the layer to dry.It is added to chloroformic solution (concentration：10mg/mL), it and will mix
Object point dye is closed on thin layer silica gel plate, and uses mixed solution (mixing ratio=85 of hexane, diethyl ether and ethyl acetate:15:2)
Expansion.Using imaging analysis instrument BAS-2500 (Fujifilm Corp. are manufactured), the part corresponding to cholesterol acid ester is measured
Radioactivity.It is similarly processed and analyzes the sample for not supplementing testing drug.According to expression formula given below, relative to not mending
The LCAT activity for filling the sample of testing drug, calculates the EC of LCAT activation50。
Equation：
The bottoms Y=+(Top-Bottom)/(1+10LogEC-X)
Wherein X represents the logarithm of the concentration of testing drug；
Y represents the response (LCAT activity) of testing drug；
Top represents maximum value (maximum platform)；
Bottom represents minimum value (minimum platform)；
EC50Represent 50% effective concentration.
Two, experimental result
The results are shown in table below for external LCAT activation experiments：
| Number | EC50(nM) |
| SDK1001 | 68.3 |
| SDK1002 | 67.5 |
| SDK1003 | 63.1 |
| SDK1004 | 58.5 |
| SDK1005 | 67.0 |
| SDK1006 | 67.3 |
| SDK1007 | 57.6 |
| SDK1008 | 56.1 |
| SDK1009 | 57.3 |
| SDK1010 | 64.2 |
As can be seen from the above table, the compounds of this invention has LCAT activations, LCAT activator can be used as pre-
Anti- or treatment cranial vascular disease (including apoplexy and cerebral infarction), coronary heart disease (including heart failure, myocardial infarction, angina pectoris, cardiac muscle
Ischemic, cardiovascular disorder and angiogenic restenosis), artery sclerosis, arteriography, peripheral vascular disease
(including diabetic vascular complications), dyslipidemia, low HDL cholesterolemia, high LDL cholesterol mass formed by blood stasis etc..
Test example 2：Internal effect experiment
One, experimental program
Each testing drug is dissolved in propylene glycol:The mixed solution of Tween 80=4/1 (v/v), and macaque is administered orally
The solution 1 or 7 days.The the 1st or the 7th day during administration, blood is collected later with administration before administration, and obtain blood plasma.
It is surveyed using commercially available assay kit (cholesterol-E Wako, Wako Pure Chemical Industries, Ltd.)
Measure the cholesterol level in blood plasma.Lipoprotein, which is analyzed, by HPLC is distributed (column：LipopropakXL, Tosoh Corp. systems
It makes).HDL cholesterol and non-HDL cholesterol levels are calculated according to following calculation expression：
Cholesterol level × (HDL cholesterol peak area/peak summation) in HDL cholesterol levels=blood plasma
Cholesterol level × (peak area of non-HDL cholesterol/peak summation) two in non-HDL cholesterol levels=blood plasma,
Experimental result
10mg/kg single doses are only disclosed in experimental result of the present invention, and the variation of HDL levels for 24 hours is administered after preceding and administration,
To prove that the ability of HDL in the compounds of this invention raising macaque blood, more experimental datas do not disclose in the present invention.With to
It is compared before medicine, the increment rate (%) of HDL levels is by before being administered and 24 hours after administration after the administration of 10mg/kg single doses
AUC determine.
| Number | Increment rate (%) |
| SDK1001 | 357.1 |
| SDK1002 | 346.8 |
| SDK1003 | 341.0 |
| SDK1004 | 399.9 |
| SDK1005 | 359.8 |
| SDK1006 | 363.0 |
| SDK1007 | 381.6 |
| SDK1008 | 409.7 |
| SDK1009 | 334.8 |
| SDK1010 | 301.9 |
As can be seen from the above table, the compounds of this invention can improve HDL horizontal forces, can to preventing or treating following disease
Can have positive effect, cranial vascular disease (including apoplexy and cerebral infarction), coronary heart disease (including heart failure, myocardial infarction, the heart twist
Bitterly, myocardial ischemia, cardiovascular disorder and angiogenic restenosis), artery sclerosis, arteriography, peripheral blood
Pipe disease (including diabetic vascular complications), dyslipidemia, low HDL cholesterolemia, high LDL cholesterol mass formed by blood stasis etc..
Claims (6)
1. a kind of general formula structure is the ester derivative and its pharmaceutically acceptable salt or solvate of formula I
Wherein：R1、R2、R3It is independently selected from H, F or CH3。
2. ester derivative formula I as described in claim 1, characterized in that be selected from following compound：
3. the answering as lecithin cholesterol acyltransferase activator of ester derivative formula I as claimed in claim 1 or 2
With.
4. application of the ester derivative formula I as claimed in claim 1 or 2 in the drug for preparing cardiovascular and cerebrovascular disease.
5. ester derivative formula I as claimed in claim 1 or 2 is preparing cranial vascular disease, coronary heart disease, artery sclerosis, artery
Hardenability heart disease, peripheral vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterol mass formed by blood stasis drug in
Application.
6. application as claimed in claim 5, which is characterized in that the cranial vascular disease includes apoplexy and cerebral infarction, the hat
Worry includes heart failure, myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorder and angiogenic restenosis.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105873928A (en) * | 2013-12-13 | 2016-08-17 | 第三共株式会社 | 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative |
| CN106916143A (en) * | 2017-03-14 | 2017-07-04 | 哈尔滨医科大学 | A kind of medicine for preventing and treating coronary heart disease and its application |
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2018
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105873928A (en) * | 2013-12-13 | 2016-08-17 | 第三共株式会社 | 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative |
| CN106916143A (en) * | 2017-03-14 | 2017-07-04 | 哈尔滨医科大学 | A kind of medicine for preventing and treating coronary heart disease and its application |
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