CN101318932A - 2'-oxatyl-5' fluorine biphenyl derivant, preparation and application thereof - Google Patents
2'-oxatyl-5' fluorine biphenyl derivant, preparation and application thereof Download PDFInfo
- Publication number
- CN101318932A CN101318932A CNA2008100406005A CN200810040600A CN101318932A CN 101318932 A CN101318932 A CN 101318932A CN A2008100406005 A CNA2008100406005 A CN A2008100406005A CN 200810040600 A CN200810040600 A CN 200810040600A CN 101318932 A CN101318932 A CN 101318932A
- Authority
- CN
- China
- Prior art keywords
- methyl
- fluoro
- biphenyl
- preparation
- butyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a 2'-carboxyl-5'-fluoro biphenyl derivative, a preparation and an application thereof. The derivative is 2-butyl-4-chlorine-1-{[2'-formic acid-5'-fluorin-(1, 1'-biphenyl)-4-yl] methyl}-1H-imidazole-5-formic acid with a molecular formula as the right formula (I). The preparation comprises the following steps that: the 2'-carboxyl-5'-fluoro biphenyl derivative is generated by 2'-carboxyl-5'-fluoro biphenyl and substituted imidazolyl through a nucleophilic substitution, wherein, 2'-methoxycarbonyl-5'-fluorin-4-methyl biphenyl is synthesized through Suzuki coupling; after the 2'-methoxycarbonyl-5'-fluorin-4-methyl biphenyl is bromized by NBS and reacts with imidazole ring, a reaction product is hydrolyzed to prepare a related compound. The compound can be used for preparing medicines for preventing or treating hypertension, coronary heart disease, diseases of heart, brain, kidney and vascular, pulmonary hypertension and other diseases.
Description
Technical field
The invention belongs to the Angiotensin II field, particularly relate to a kind of 2 '-carboxyl-5 '-fluorine biphenyl derivant, its preparation and application.
Background technology
(rennin-angiotensin system's renin-angiotensin system RAS) plays an important role in hypertensive generation, development.It can make vascular smooth muscle cell proliferation, myocardial cell's hypertrophy, causes changes such as vessel wall thickening, vascular resistance increase and left ventricular hypertrophy.The key link of RAS is Angiotensin II (angiotensin II, Ang II), and AngII can discern its specificity AT acceptor, and playing a role by certain signal pathway makes elevation of blood pressure.
AngII is an octapeptide structure (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), early stage angiotensin antagonist (ARB), as Saralasin (Saralasin), its structure is similar to A II, and different is that conversion has been carried out in the position of L-Ala in the A II molecule and tyrosine.But this class peptides, it is oral invalid, and the metabolism instability, and very big restriction is arranged in clinical application.
Sweden ratified to have gone on the market first non-peptide class and the strong AngII receptor antagonist losartan (Losartan) of selectivity in 1994, had comprised cyclohexyl biphenyl and substituted imidazole group that tetrazole replaces in its structure.This medicine is that first can oral specific AT1 receptor blocking agent, bioavailability 33%.Compd E xp7711 is the active metabolism of losartan in the body class.
The ARBs that has gone on the market at present all is with the structure of this medicine non-peptide compound for " source ".Concentrate on the modification of imidazole ring for the research major part of ARBs.
And there is certain defective in tetrazole in synthetic and metabolism, need use toxic explosive raw material sodiumazide as synthetic tetrazole; Tetrazole in vivo easily with the form of glucosiduronate by metabolism, thereby cause medicine lifetime in vivo to shorten.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of 2 '-carboxyl-5 '-fluorine biphenyl imdazole derivatives, its preparation and application, raw material convenient sources in the preparation of this compound, preparation is simple, cost is low, and guaranteed the existence of biphenyl ortho position acidic-group, do not influence the activity of medicine, solved defective of the prior art.
2 '-carboxyl-5 ' of the present invention-fluorine biphenyl imdazole derivatives is 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid, its structure is as follows:
This compound is a class angiotensin II receptor antagonists, 168～170 ℃ of fusing points.This compound is soluble in organic solvents such as methylene dichloride, chloroform, ethyl acetate, toluene.
Principle of the present invention is to utilize the acidity of the strong electrophilic function influence biphenyl carboxylic acids of fluorine atom, fluorinated organic compound has higher fat-soluble and hydrophobicity simultaneously, can promote compound absorption and transmission speed in vivo, its physiological action is changed.
2 '-carboxyl-5 ' of the present invention-fluorine biphenyl imdazole derivatives, be to generate by 2 '-carboxyl-5 '-fluorine biphenyl and substituted imidazole base nucleophilic substitution, by suzuki coupling Synthetic 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl, then with behind the NBS bromo and after the imidazole ring reaction, hydrolysis prepares corresponding compounds, and concrete preparation process comprises:
The preparation of (1) 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl
Mol ratio is 0.8～0.9: 1 4-methylphenylboronic acid and 2-bromo-5-fluorophenyl carbamate, at K
2CO
3, catalyst P h
3P, catalyst P d (OAC)
2Under mixed solvent, 95～105 ℃ of heating reflux reactions 1.5～2.5 hours separate organic phase, concentrate the back column chromatography for separation, 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl;
Wherein, K
2CO
3With the mole ratio of 4-methylphenylboronic acid be 6～8: 1, catalyst P h
3The mole ratio of P and 4-methylphenylboronic acid is 0.6～0.8: 1, and catalyst P d (OAC)
2With the mole ratio of 4-methylphenylboronic acid be 0.4～0.6: 1;
Mixed solvent is 1, the mixture of 4-dioxane and water, and the mixed volume ratio is 4: 1, the amount ratio of this mixed solvent and 4-methylphenylboronic acid is 5～6ml: 1mmol;
Weighting agent in the column chromatography for separation is a silica gel H, and eluent is a sherwood oil: the mixed solvent of ethyl acetate, blending ratio scope are 150: 1～100: 1;
The preparation of (2) 2 '-methoxycarbonyls-5 '-fluoro-4-bromomethylbiphenyl
Mol ratio is 6～8: 7～8: 2 '-methoxycarbonyl-5 ' of 1-fluoro-4-methyl diphenyl, N-bromo-succinimide (NBS) and Diisopropyl azodicarboxylate (AIBN), in the presence of hexanaphthene, wherein, the consumption of 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl and hexanaphthene is 1g: 20～25ml, 75～85 ℃ of heating reflux reactions are after 2.5～3.5 hours, cooling back suction filtration, the solid washed with dichloromethane, collect organic phase, be spin-dried for the back column chromatography for separation, get 2 '-methoxycarbonyl-5 '-fluoro-4-bromomethylbiphenyl;
Weighting agent is a silica gel H in the column chromatography for separation, and eluent is a sherwood oil: the mixed solvent of ethyl acetate, blending ratio scope are 150: 1～100: 1;
(3) 2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formaldehyde
Under the nitrogen protection, mol ratio is 0.7～0.8: 0.6～0.7: 1 2-butyl-4-chloro-1H-imidazoles-5-formaldehyde, 2 '-methoxycarbonyl-5 '-fluoro-4-bromomethylbiphenyl and salt of wormwood, in the presence of acetonitrile, wherein, the amount ratio of acetonitrile and 2-butyl-4-chloro-1H-imidazoles-5-formaldehyde is 25ml: 7.5～8mmol, 40～50 ℃ of stirring reactions suction filtration after 4～5 hours, filter residue washs with ethyl acetate, collect filtrate, be spin-dried for, column chromatography for separation gets 2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formaldehyde;
Weighting agent is a silica gel H in the column chromatography for separation, and eluent is a sherwood oil: the mixed solvent of ethyl acetate, blending ratio scope are 3: 1～1: 1.
(4) 2-butyl-4-chloro-1-{[2 '-methyl-formiate-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formic acid
0.8～0.9mmol2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-and the 4-yl] methyl }-1H-imidazoles-5-formaldehyde and 10～15ml propyl carbinol, at room temperature drip the clorox of 10～15ml and the mixed aqueous solution of SODIUM PHOSPHATE, MONOBASIC, wherein, the concentration of clorox and SODIUM PHOSPHATE, MONOBASIC is respectively 0.7～0.8mol/L and 0.5～0.6mol/L, stirred 12～15 hours, separate organic phase, the water ethyl acetate extraction, merge organic layer, drying, recrystallization, get white solid 2-butyl-4-chloro-1-{[2 '-methyl-formiate-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid;
(5) 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formic acid
Mol ratio is 2-butyl-4-chloro-1-{[2 '-methyl-formiate-5 '-fluoro-(1 of 1: 3～4,1 '-biphenyl)-and the 4-yl] methyl }-1H-imidazoles-5-formic acid and sodium hydroxide, under methanol aqueous solution, 60～70 ℃ of stirring reactions 3～5 hours, wherein, methanol aqueous solution is that volume ratio is 3: 1 the methyl alcohol and the mixed solution of water, the amount ratio of methanol aqueous solution and sodium hydroxide is 1ml: 0.6～0.7mg, be spin-dried for methyl alcohol, water is 2%～4% dilute hydrochloric acid with adding mass concentration after the ether washing, the adularescent material is separated out, suction filtration, after the solid matter drying, recrystallization, get 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid white crystal.
2 '-carboxyl-5 ' of the present invention-fluorine biphenyl imdazole derivatives can be used for preparing the medicine of prevention or diseases such as treatment hypertension, coronary heart disease, heart brain and kidney blood vessel diseases and pulmonary hypertension.
Beneficial effect of the present invention:
1) compound (I) mainly is the modification to cyclohexyl biphenyl, with respect to for, the biphenyl raw material of carboxylic acid-substituted is easy to get, preparation is simple, can reduce cost greatly, has guaranteed the existence of biphenyl ortho position acidic-group simultaneously again, does not influence the activity of medicine;
2) from the structure activity relationship analysis of losartan, strong more its biological activity of the acidity of biphenyl ortho position group is strong more, therefore, introduces the F atom on cyclohexyl biphenyl, utilizes the sucting electronic effect of F atom to influence benzoic acidity;
3) in the spontaneous hypertensive rat experiment, find that tentatively this compounds has certain antihypertensive effect.
Description of drawings
Fig. 1 is 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid
1H NMR spectrogram;
Fig. 2 is 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-mass spectrum of 1H-imidazoles-5-formic acid.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
The preparation of (1) 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl
Adding 4-methylphenylboronic acid in the 250ml reaction flask (3.40g, 25mmol), 2-bromo-5-fluorophenyl carbamate (6.99g, 30mmol), excessive K
2CO
3(17.3g, 0.175mol), Ph
3P (4.8g, 0.018mol) and Pd (OAC)
2(2.8g 0.013mol), adds 150mL 1, the mixed solvent of 4-dioxane and distilled water (volume ratio is 4: 1).100～105 ℃ of reflux 2 hours are separated organic phase, concentrate back silica gel H column chromatography for separation (eluent is a sherwood oil: ethyl acetate=150: 1～100: 1), product (
) 4.62g, productive rate 75.8%.
The preparation of (2) 2 '-methoxycarbonyls-5 '-fluoro-4-bromomethylbiphenyl
Add in the 50ml reaction flask 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl (1g, 4.10mmol), NBS (0.77g, 4.30mmol), AIBN (96mg, 0.58mmmol), hexanaphthene 20ml, 75～85 ℃ of reflux 3 hours, stopped reaction, cooling back suction filtration, the solid washed with dichloromethane, collect organic phase, be spin-dried for back silica gel H column chromatography for separation (eluent is a sherwood oil: ethyl acetate=150: 1～100: 1), product (
) 0.85g, productive rate 64.23%.
(3) 2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formaldehyde
Adding 2-butyl-4-chloro-1H-imidazoles-5-formaldehyde in the 100ml dry reaction bottle (1.44g, 7.70mmol), 2 '-methoxycarbonyl-5 '-fluoro-4-bromomethylbiphenyl (2.26g; 7mmol), and salt of wormwood (1.45g, 10.5mmol); acetonitrile 25ml, nitrogen protection is behind 40～50 ℃ of stirring reaction 4～5h; suction filtration, filter residue washs with ethyl acetate, collects filtrate; be spin-dried for; (eluent is a sherwood oil to the silica gel H column chromatography for separation: ethyl acetate=3: 1～1: 1), get product 0.93g, yield 31.14%.
2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formaldehyde, structural formula is
Its collection of illustrative plates is as follows:
1HNMR(400MHz，CDCl
3，δ)：9.94(s，1H，CHO)，7.58(dd，1H，J
1＝9.2Hz，J
2＝2.8Hz，Ph)，7.22～7.32(m，4H，Ph)，7.08(d，2H，J＝8.4Hz，Ph)，5.23(s，2H，Ph
CH 2 )，3.67(s，3H，PhCOO
CH 3 )，2.67(t，2H，J＝8.0Hz，C
H 2 CH
2CH
2CH
3)，1.71(quint，2H，J＝8.0Hz，CH
2C
H 2 CH
2CH
3)，1.37(sext，2H，J＝8.0Hz，CH
2CH
2C
H 2 CH
3)，0.90(t，3H，J＝8.0Hz，CH
2CH
2CH
2C
H 3 )；
13CNMR(400MHz，CDCl
3，δ)：182.97，169.50，165.32，162.85，152.70，143.07，140.18，136.69，135.71，134.85，134.33，131.63，128.31，127.27，120.87，119.36，54.50，49.22，32.01，31.53，29.86，24.69，15.99，2.3；
MS(ESI)m/z：429[M+1]
+，461[M+CH
3OH]
+，483[M+CH
3ONa]
+。
(4) 2-butyl-4-chloro-1-{[2 '-methyl-formiate-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formic acid
Add 2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-4-yl in the 50ml flask] methyl }-1H-imidazoles-5-formaldehyde (0.37g, 0.86mmol), propyl carbinol (10ml), drip under the room temperature clorox (0.67g, 7.37mmol), SODIUM PHOSPHATE, MONOBASIC (0.68g, 5.65mmol) aqueous solution 10ml, stir 12～14h after, separate organic phase, the water ethyl acetate extraction, merge organic layer, drying, recrystallization, get white solid 0.34g, yield 90%.
2-butyl-4-chloro-1-{[2 '-methyl-formiate-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid, structural formula is
Its collection of illustrative plates is as follows:
1HNMR(400MHz，CDCl
3，δ)：7.57(dd，1H，J1＝8.8Hz，J2＝2.8Hz，Ph)，7.22～7.32(m，4H，Ph)，7.08(d，2H，J＝8.0Hz，Ph)，5.23(s，2H，PhCH
2)，3.66(s，3H，COO
CH 3 )，2.73(t，2H，J＝8.0Hz，
CH 2 CH
2CH
2CH
3)，1.65(quint，2H，J＝8.0Hz，CH
2 CH 2 CH
2CH
3)，1.36(sext，2H，J＝8.0Hz，CH
2CH
2 CH 2 CH
3)，0.86(t，3H，J＝8.0Hz，CH
2CH
2CH
2 CH 3 )；
13CNMR(400MHz，CDCl
3，δ)：169.57，165.30，162.83，151.396，142.97，140.23，135.88，134.81，134.42，131.57，128.29，120.95，119.43，54.52，49.56，31.82，29.63，24.63，15.99；
MS(ESI)m/z：445[M+1]+。
(5) 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formic acid
Add 2-butyl-4-chloro-1-[[2 '-methyl-formiate-4 '-fluoro-(1 in the 50ml reaction flask, 1 '-biphenyl)-and the 4-yl] methyl]-1H-imidazoles-5-formic acid (49mg, 0.11mmo1), sodium hydroxide (13.2mg, 0.33mmol), methyl alcohol 15ml, distilled water 5ml, 60～70 ℃ of stirring reactions 3～5 hours, be spin-dried for methyl alcohol, water is 2%～4% dilute hydrochloric acid neutralization with adding mass concentration after the ether washing, and the adularescent material is separated out, suction filtration, after the solid matter drying, recrystallization gets white crystal 45mg, yield 95%.
2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid, its structural formula is
Its collection of illustrative plates is as follows:
1HNMR(400MHz，DMSO，δ)：7.49(dd，1H，J
1＝9.2Hz，J
2＝1.6Hz，Ph)，7.36～7.45(m，2H，Ph)，7.32(d，2H，J＝8.0Hz，Ph)，7.05(d，2H，J＝12.8Hz，Ph)，5.30(s，2H，Ph
CH 2 )，2.63(t，2H，J＝7.6Hz，C
H 2 CH
2CH
2CH
3)，1.55(quint，2H，J＝7.6Hz，CH
2C
H 2 CH
2CH
3)，1.28(sext，2H，J＝7.6Hz，CH
2CH
2C
H 2 CH
3)，0.82(t，3H，J＝7.6Hz，CH
2CH
2CH
2C
H 3 )；
13CNMR(400MHz，DMSO，δ)：170.92，165.44，164.99，162.55，151.21，142.10，139.52，137.52，136.93，135.45，131.67，129.37，128.76，125.19，120.62，120.41，118.63，118.40，49.14，31.47，29.25，24.41，16.35；
MS(ESI)m/z：431[M+1]
+。
The experiment of embodiment 2 antihypertensive drugs screening active ingredients
Laboratory animal:
30 of spontaneous hypertensive rats (SHR), health, ♀ ♂ half and half (female unpregnancy), available from Shanghai must be triumphant laboratory animal company limited, conformity certification number: Shanghai is moving closes card card word No. 152;
Be subjected to the reagent product:
Antihypertensive activity compound 2-normal-butyl-3-{[2 '-carboxyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone (compound 1)
Positive control drug: losartan, clinical consumption is 50mg/kg, if body weight for humans is 60kg, human dosage is 5/6mg/kg, be scaled rat dosage 5mg/kg, the losartan molecular weight is 461, and being converted into volumetric molar concentration is 1.86mol/L, positive control drug is equivalent to dosage in the effect experiment (ratio of basic, normal, high dosage is 1: 2: 4), is set at 3.72mol/L.
Experimental technique:
Select 30 spontaneous hypertensive rats (SHR) model for use, be divided into blank group, positive controls, compound 1 administration group, do not have the wound blood pressure transducer with animalcule and after carrier wave amplifies, be connected to the clear-headed free moving animals blood pressure recording analytical system (Shanghai of MPA-HBBS type, Alcott), the subcutaneous insertion needle electrode of four limbs is connected to alternating current amplifier and is used for monitoring standard two lead electrocardiogram.The tail sleeve is sent out and is measured clear-headed rat caudal artery mean arterial pressure (MAP), systolic pressure (SAP), diastolic pressure (DAP), heart rate (HR) and electrocardiogram(ECG (ECG).
During test compound 1 is mixed with the aqueous solution that concentration is 3.72mol/L.Positive control drug losartan sheet is mixed with the aqueous solution that concentration is 3.72mol/L during test.Each treated animal is pressed above-mentioned dosage gastric infusion 1 time every day, and blank group is given the physiological saline with volume, 2 weeks of continuous use.
The caudal artery of the non-invasive measurement rat blood pressure method of beating is adopted in blood pressure determination, all rats respectively at administration before and 1 month each measuring blood pressure 1 time after the administration, each blood pressure is got the mean value of measuring for 3 times.
The mensuration of endothelin level (ET), NO: adopt 2ml, inject and contain 10% the EDTA disodium 30 and the test tube of Trypsin inhibitor,Trasylol 40, mixing, 4 ℃, the centrifugal 10min of 3000r/min, separated plasma is put in one 20 ℃ the refrigerator and is preserved.Make sample place room temperature to melt again before the mensuration, 4 ℃ once more, the centrifugal 5mn of 3000r/min gets supernatant and measures, and operates from the strictness of reagent specification sheets by individual then.
Data processing: all experimental datas are all with mean ± standard deviation (x ± SD) expression, the variance analysis that blood pressure, NO and ET relatively design with completely random between each group after the medication, do not wait as each group population mean, the multiple comparisons of building with a plurality of sample averages again, promptly q checks and handles.
Experimental result:
Blood pressure result: to treat preceding blood pressure difference as variable, relatively there were significant differences (P＜0.01) for each class mean, again through the q of multiple sample mean testing identity, relatively there were significant differences (P＜0.01) for 1 group of compound and positive control and blank group, 1 group of compound and positive controls relatively do not have significant difference (P＜0.01), illustrate that compound 1 has tangible hypotensive effect, active suitable with losartan.
Nitrogen protoxide (NO) result: the NO value illustrates that through variance analysis (P＜0.05) relatively there were significant differences between each group after the medication, and again through multiple sample mean q testing identity, compound obviously is better than other groups (P＜0.05) for 1 group
Endothelin (ET) result: the ET value is through variance analysis (P＜0.01) after the medication, and illustrating between each group relatively has utmost point significant difference, and again through the q of multiple sample mean testing identity, compound obviously is better than other groups (P＜0.01) for 1 group.
Respectively organize blood pressure, nitrogen protoxide (NO) and the comparison of endothelin (ET) value (x ± N=10) after table 1. experiment
| Group | Blood pressure difference (mmHg) | ET(pg/ml) | NO(μmol/L) |
| Blank group | 5.88±4.62 | 94.25±34.24 | 11.57±2.35 |
| Positive control (losartan) group | 44.52±25.48 ** | 58.11±20.45 | 11.36±4.23 |
| 1 group of compound | 45.72±10.33 ** | 45.69±13.51 **## | 15.51±5.34# |
Annotate: compare with the blank group:
*P＜0.01; Compare with positive controls: #P＜0.05, ##P＜0.01
Claims (8)
1. 2 '-carboxyl-5 '-fluorine biphenyl imdazole derivatives, it is characterized in that: this derivative is 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid, its structure is as follows:
168～170 ℃ of this melting point compounds.
2. the preparation method of 2 '-carboxyl-5 '-fluorine biphenyl imdazole derivatives comprises step:
The preparation of (1) 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl
Mol ratio is 0.8～0.9: 1 4-methylphenylboronic acid and 2-bromo-5-fluorophenyl carbamate, at K
2CO
3, catalyst P h
3P, catalyst P d (OAC)
2Under mixed solvent, 95～105 ℃ of heating reflux reactions 1.5～2.5 hours separate organic phase, concentrate the back column chromatography for separation, 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl, wherein, K
2CO
3With the mole ratio of 4-methylphenylboronic acid be 6～8: 1, catalyst P h
3The mole ratio of P and 4-methylphenylboronic acid is 0.6～0.8: 1, and catalyst P d (OAC)
2With the mole ratio of 4-methylphenylboronic acid be 0.4～0.6: 1, mixed solvent is 1, the mixture of 4-dioxane and water, the mixed volume ratio is 4: 1, the amount ratio of this mixed solvent and 4-methylphenylboronic acid is 5～6ml: 1mmol;
The preparation of (2) 2 '-methoxycarbonyls-5 '-fluoro-4-bromomethylbiphenyl
Mol ratio is 6～8: 7～8: 2 '-methoxycarbonyl-5 ' of 1-fluoro-4-methyl diphenyl, N-bromo-succinimide and Diisopropyl azodicarboxylate, in the presence of hexanaphthene, 75～85 ℃ of heating reflux reactions are after 2.5～3.5 hours, cooling, suction filtration, collect organic phase, be spin-dried for the back column chromatography for separation, get 2 '-methoxycarbonyl-5 '-fluoro-4-bromomethylbiphenyl;
(3) 2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formaldehyde
Under the nitrogen protection, mol ratio is 0.7～0.8: 0.6～0.7: 1 2-butyl-4-chloro-1H-imidazoles-5-formaldehyde, 2 '-methoxycarbonyl-5 '-fluoro-4-bromomethylbiphenyl and salt of wormwood, in the presence of acetonitrile, 40～50 ℃ of stirring reactions suction filtration after 4～5 hours, collect filtrate, be spin-dried for column chromatography for separation, get 2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formaldehyde;
(4) 2-butyl-4-chloro-1-{[2 '-methyl-formiate-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formic acid
0.8～0.9mmol 2-butyl-4-chloro-1-{[2 '-methyl-formiate base-5 '-fluoro-(1,1 '-biphenyl)-and the 4-yl] methyl }-1H-imidazoles-5-formaldehyde and 10～15ml propyl carbinol, at room temperature drip the clorox of 10～15ml and the mixed aqueous solution of SODIUM PHOSPHATE, MONOBASIC, stirred 12～15 hours, organic phase drying after the separation, recrystallization gets 2-butyl-4-chloro-1-{[2 '-methyl-formiate-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid;
(5) 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-preparation of 1H-imidazoles-5-formic acid
Mol ratio is 2-butyl-4-chloro-1-{[2 '-methyl-formiate-5 '-fluoro-(1 of 1: 3～4,1 '-biphenyl)-and the 4-yl] methyl }-1H-imidazoles-5-formic acid and sodium hydroxide, under methanol aqueous solution, 60～70 ℃ of stirring reactions 3～5 hours are spin-dried for methyl alcohol, water adds dilute hydrochloric acid after washing with ether, suction filtration, after the solid matter drying, recrystallization, get 2-butyl-4-chloro-1-{[2 '-formic acid-5 '-fluoro-(1,1 '-biphenyl)-4-yl] methyl }-1H-imidazoles-5-formic acid.
3. the preparation method of 2 '-carboxyl-5 ' according to claim 2-fluorine biphenyl imdazole derivatives, it is characterized in that: in the described step (1), weighting agent in the column chromatography for separation is a silica gel H, eluent is a sherwood oil: the mixed solvent of ethyl acetate, blending ratio scope are 150: 1～100: 1.
4. the preparation method of 2 '-carboxyl-5 ' according to claim 2-fluorine biphenyl imdazole derivatives is characterized in that: in the described step (2), the consumption of 2 '-methoxycarbonyl-5 '-fluoro-4-methyl diphenyl and hexanaphthene is 1g: 20～25ml; Weighting agent in the column chromatography for separation is a silica gel H, and eluent is a sherwood oil: the mixed solvent of ethyl acetate, blending ratio scope are 150: 1～100: 1.
5. the preparation method of 2 '-carboxyl-5 ' according to claim 2-fluorine biphenyl imdazole derivatives, it is characterized in that: in the described step (3), the amount ratio of acetonitrile and 2-butyl-4-chloro-1H-imidazoles-5-formaldehyde is 25ml: 7.5～8mmol, weighting agent in the column chromatography for separation is a silica gel H, eluent is a sherwood oil: the mixed solvent of ethyl acetate, blending ratio scope are 3: 1～1: 1.
6. the preparation method of 2 '-carboxyl-5 ' according to claim 2-fluorine biphenyl imdazole derivatives is characterized in that: in the described step (4), the concentration of clorox and SODIUM PHOSPHATE, MONOBASIC is respectively 0.7～0.8mol/L and 0.5～0.6mol/L.
7. the preparation method of 2 '-carboxyl-5 ' according to claim 2-fluorine biphenyl imdazole derivatives, it is characterized in that: in the described step (5), methanol aqueous solution is that volume ratio is 3: 1 the methyl alcohol and the mixed solution of water, and the amount ratio of methanol aqueous solution and sodium hydroxide is 1ml: 0.6～0.7mg; The mass concentration of dilute hydrochloric acid is 2%～4%.
8. 2 '-carboxyl-5 '-fluorine biphenyl imdazole derivatives is applied to prepare the medicine that prevents or treat hypertension, coronary heart disease, heart brain and kidney blood vessel diseases and pulmonary hypertension disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100406005A CN101318932A (en) | 2008-07-15 | 2008-07-15 | 2'-oxatyl-5' fluorine biphenyl derivant, preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100406005A CN101318932A (en) | 2008-07-15 | 2008-07-15 | 2'-oxatyl-5' fluorine biphenyl derivant, preparation and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101318932A true CN101318932A (en) | 2008-12-10 |
Family
ID=40179235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100406005A Pending CN101318932A (en) | 2008-07-15 | 2008-07-15 | 2'-oxatyl-5' fluorine biphenyl derivant, preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101318932A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102320971A (en) * | 2011-07-14 | 2012-01-18 | 浙江禾田化工有限公司 | Preparation method of alpha-(2-brooethyl)-beta-methoxy-methyl acrylate |
| CN106460059A (en) * | 2014-06-03 | 2017-02-22 | 诺华股份有限公司 | Pulmonary hypertension biomarker |
-
2008
- 2008-07-15 CN CNA2008100406005A patent/CN101318932A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102320971A (en) * | 2011-07-14 | 2012-01-18 | 浙江禾田化工有限公司 | Preparation method of alpha-(2-brooethyl)-beta-methoxy-methyl acrylate |
| CN106460059A (en) * | 2014-06-03 | 2017-02-22 | 诺华股份有限公司 | Pulmonary hypertension biomarker |
| US12012636B2 (en) | 2014-06-03 | 2024-06-18 | Novartis Ag | Pulmonary hypertension biomarker |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103159680A (en) | Imidazole diketone compound and application thereof | |
| CN110092779B (en) | Substituted phenyl compound and application thereof | |
| CN106432191A (en) | Novel pyrroles derivative as well as preparation method and pharmaceutical application thereof | |
| RU2635564C2 (en) | Composition for treatment of hypertension and/or fibrosis | |
| CN112552272B (en) | Coumarin compound, preparation method and application thereof, and pharmaceutical composition | |
| CN101798300B (en) | N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like | |
| JP2010511636A (en) | Salt of imidazole-5-carboxylic acid derivative, production method and pharmaceutical composition thereof | |
| He et al. | Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus | |
| CN113444069B (en) | 2-aryl-4- (1H-pyrazol-3-yl) pyridine LSD1/HDAC double-target inhibitor | |
| CN105814039A (en) | Fluorophenyl pyrazol compounds | |
| CN104277029A (en) | Acridine-1, 2, 3-triazole type compound and preparation method and application thereof | |
| CN101318932A (en) | 2'-oxatyl-5' fluorine biphenyl derivant, preparation and application thereof | |
| CN103145697A (en) | Nitrobenzimidazole compound, preparation method and application thereof | |
| JP2008506722A (en) | Cis-1,2-substituted stilbene derivatives and their use in the manufacture of a medicament for the treatment and / or prevention of diabetes | |
| CN101318934B (en) | 2'-oxatyl-4'fluorine biphenyl heterocycle ketone compound, preparation and application thereof | |
| CN102558064B (en) | Antihypertensive compound, and its preparation method, application and pharmaceutically acceptable salts and solvates | |
| CN102796083B (en) | Assorted spirocyclic ketone N-Phenylindole compounds, its preparation method and application | |
| CN104774197B (en) | A kind of preparation method of benzimidizole derivatives | |
| CN103040815B (en) | Application of 2,4,6-triisopropylbenzene compounds in preparation of medicines for treating diabetes | |
| CN111039880A (en) | Application of miconazole and derivative thereof as TGR5 agonist | |
| CN107400089A (en) | The preparation method and applications of the twin medicine of aspirin of anti-cerebral apoplexy based on the double target spots of TXA2/ROS | |
| CN103408554A (en) | Hypertensive activity reducing pyrrole coumarins compound and preparation method thereof | |
| CN110423213B (en) | Apremilast derivative and preparation method and application thereof | |
| CN110092799B (en) | Cyclic compound, preparation method and application thereof | |
| CN109422799A (en) | Docetaxel anti-liver cancer and anti-targeted prodrug and its pharmaceutical usage |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20081210 |