CN101318934B - 2'-oxatyl-4'fluorine biphenyl heterocycle ketone compound, preparation and application thereof - Google Patents
2'-oxatyl-4'fluorine biphenyl heterocycle ketone compound, preparation and application thereof Download PDFInfo
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- CN101318934B CN101318934B CN2008100405869A CN200810040586A CN101318934B CN 101318934 B CN101318934 B CN 101318934B CN 2008100405869 A CN2008100405869 A CN 2008100405869A CN 200810040586 A CN200810040586 A CN 200810040586A CN 101318934 B CN101318934 B CN 101318934B
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Abstract
The invention relates to a 2'-carboxyl-4'-fluorobiphenyl-spiro-ketone compound, a preparation method and an application thereof. The structural formula of the compound is shown in a right formula (I). The preparation comprises the following steps that: 2'-methoxycarbonyl-5'-fluorin-4-methyl biphenyl is synthesized through Suzuki coupling; the compound I is generated after the 2'-methoxycarbonyl-5'-fluorin-4-methyl biphenyl is bromized by N-bromobutanimide and reacts with spiro-ketone. The application is as follows: the compound can be used for preparing drugs for preventing or treating hypertension, coronary heart disease, diseases of heart, brain, kidney and vascular, pulmonary hypertension and other diseases, and is an antagonist of an angiotensin II acceptor. The drug of the invention increases the lifespan in a body, improves the biological activity, and has the advantages of simple preparation method and low cost.
Description
Technical field
The present invention relates to a kind of 2 '-carboxyl-4 '-fluorine biphenyl derivant and preparation thereof and application, relate in particular to the assorted spirocyclic ketone compound of a kind of 2 '-carboxyl-4 '-fluorine biphenyl and preparation and application.
Background technology
Because the existence of Angiotensin II (AngII) causes it to play considerable effect in the regulate process of blood pressure, the target spot that therefore is used as the step-down treatment is subjected to extensive studies in the renin-angiotensin system (RAS).
From 1994, angiotensin-ii receptor (AT1 hypotype) the antagonist losartan (Losartan) that Dupont group has researched and developed first non-peptide class and had an Orally active afterwards, a series of similar angiotensin II receptor antagonists are developed listing in succession.As Irb (Ibersartan) that goes on the market respectively in valsartan (valsartan), in September, 1997 and the December of in December, 1996 listing and Candesartan (Candesartan) and the telmisartan (Telmisartan) that goes on the market respectively in Yi Pushatan (Eprosartan), in June, 1998 and November, (Olmesartan) of in April, 2002 listing etc.
The losartan structure roughly can divide three parts to form: xenyl, imidazolyl and tetrazole group.This three parts group with the combination of acceptor in play a different role.And mainly concentrate on modification to imidazolyl, for example Irb (irbesartan) of listing in 1997 for the major part research of this class formation.In the structure of Irb (irbesartan), adopted the alkyl of large volume to replace chlorine atom in the losartan structure, occupy bigger hydrophobic space when making medicine and AT1 receptors bind; In Irb (irbesartan) structure, the carbonyl on the imidazole ring is similar to the CH of losartan simultaneously
2The OH group can form hydrogen bond with the AT1 acceptor interaction equally.
In addition, 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, thereby need to adopt other group come the substituted tetrazole group.
Summary of the invention
The purpose of this invention is to provide the assorted spirocyclic ketone compound of a kind of 2 '-carboxyl-4 '-fluorine biphenyl and preparation and application.By structure based on Irb (Irbesartan), in structure, substitute the tetrazole group with carboxyl, increase medicine lifetime in vivo, the biphenyl raw material of carboxylic acid-substituted is easy to get simultaneously, preparation is simple, can reduce cost greatly, can guarantee the existence of biphenyl ortho position acidic-group simultaneously again, not influence the activity of medicine.In addition, on cyclohexyl biphenyl, introduce the F atom again, utilize the sucting electronic effect of F atom to influence benzoic acidity, strengthen biological activity.
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 increase transmission speed in vivo, its physiological action is changed.
The preparation method of the assorted spirocyclic ketone compound of 2 '-carboxyl-4 ' of the present invention-fluorine biphenyl, be by Suzuki coupling Synthetic 2 '-methoxycarbonyl-4 '-fluoro-4-methyl diphenyl, use behind N-bromo-succinimide (NBS) bromo then and the reaction of assorted spirocyclic ketone, generate Compound I, concrete reaction equation is as follows:
2 '-carboxyl-4 ' of the present invention-fluorine biphenyl spirocyclic ketone compound of mixing is 2-normal-butyl-3-{[2 '-carboxyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1, in 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, structure is as follows:
This compound is a class angiotensin II receptor antagonists, and its fusing point is 158～160 ℃, is soluble in organic solvents such as methylene dichloride, chloroform, ethyl acetate, toluene.
The preparation method of the assorted spirocyclic ketone compound of 2 '-carboxyl-4 ' of the present invention-fluorine biphenyl specifically may further comprise the steps: 1) Synthetic 2 '-methoxycarbonyl-4 '-fluoro-4-methyl diphenyl
Add 25～30mmol 4-methylphenylboronic acid, 30～35mmol 2-bromo-5-fluorophenyl carbamate and excessive K in the reaction flask
2CO
3, catalytic amount Ph
3P and Pd (OAC)
2, add 140～150mL volume ratio simultaneously and be 4: 11, the mixed solvent of 4-dioxane and water, 95～110 ℃ of reflux 1.5～2.5 hours are separated organic phase, concentrate the back column chromatography for separation, 2 '-methoxycarbonyl-4 '-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,
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;
2) synthetic 4 '-fluoro-4-methyl diphenyl-2 '-formic acid
10～15mmol 2 '-methoxycarbonyl-4 '-fluoro-4-methyl diphenyl, 30～35mmol sodium hydroxide, methyl alcohol 20～30mL, water 10～15mL, 55～65 ℃ of reflux are after 4.5～5.5 hours, be spin-dried for methyl alcohol, the water extracted with diethyl ether, discard organic phase, it is the neutralization of 2%～4% dilute hydrochloric acid that water adds mass concentration, gets white mass 4 '-fluoro-4-methyl diphenyl-2 '-formic acid; 3) Synthetic 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-methyl diphenyl
The CH that adds 4 ' of 8.0～8.5mmol-fluoro-4-methyl diphenyl-2 '-formic acid and 15～20mL in the reaction flask
2Cl
2Ice bath drips oxalyl chloride down, and (10～12mmoL), stirring at room 3～4 hours is spin-dried for reaction solution, add anhydrous tetrahydro furan 20～25mL, ice bath drips potassium tert.-butoxide down, and (8.0～8.5mmol), stirring at room is 1～2 hour after dropwising, and reaction solution is poured in the frozen water, ethyl acetate extraction, collect organic phase, drying, column chromatography for separation gets product;
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 120: 1～150: 1;
4) Synthetic 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-bromomethylbiphenyl
Add 3.5～4.0mmol 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-methyl diphenyl, 3.8～4.2mmol N-bromo-succinimide (NBS), 0.50～0.55mmol Diisopropyl azodicarboxylate (AIBN), 20～30mL hexanaphthene in the reaction flask, after the reaction in 3～4 hours of 75～85 ℃ of reflux, after reacting completely, cooling, suction filtration, the solid washed with dichloromethane is collected organic phase, is spin-dried for the back column chromatography for separation;
Column chromatography for separation, weighting agent are silica gel H, and eluent is a sherwood oil: the mixed solvent of ethyl acetate, blending ratio scope are 150: 1～200: 1;
5) Synthetic 2-normal-butyl-3-{[2 '-tertbutyloxycarbonyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone
Under the nitrogen protection, 2.6 the 2-normal-butyl-1 of～2.7mmol, 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, mass concentration are 60% sodium hydride 6～7mmol, anhydrous tetrahydro furan (THF) 10～20mL, 45～55 ℃ were stirred 0.5～1 hour, the cooling back drips the tetrahydrofuran solution 20～25mL of 0.09～0.11mol/L2 '-tertbutyloxycarbonyl-4 '-fluoro-4-bromomethylbiphenyl, drip and finish, continue reaction after 2.5～3.5 hours, reaction solution is poured in the frozen water, ethyl acetate extraction is collected organic phase, dry back column chromatography for separation;
Column chromatography for separation, weighting agent are silica gel H, and eluent is a sherwood oil: the mixed solvent of ethyl acetate, blending ratio scope are 4: 1～2: 1;
6) Synthetic 2-normal-butyl-3-{[2 '-carboxyl-4 '-fluorine (1,1-biphenyl)-and the 4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-add 2-normal-butyl-3-{[2 '-tertbutyloxycarbonyl-4 '-fluorine (1 of 0.6～0.7mmol in 1-alkene-4-reactive ketone bottle, 1-biphenyl)-and the 4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, 1～2mL CF
3COOH, 2～4mL methylene dichloride, stirring at room 1.5～2.5 hours is removed and to be desolvated, and adds ether, white 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.
The assorted spirocyclic ketone compound of 2 '-carboxyl-4 ' of the present invention-fluorine biphenyl 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:
1) substitutes the tetrazole group with carboxyl in the structure, increase medicine lifetime in vivo;
2) the biphenyl raw material of carboxylic acid-substituted is easy to get, and preparation is simple, can reduce cost greatly, can guarantee the existence of biphenyl ortho position acidic-group simultaneously again, does not influence the activity of medicine;
3) on cyclohexyl biphenyl, introduce the F atom, utilize the sucting electronic effect of F atom to influence benzoic acidity, strengthen biological activity;
4) in the spontaneous hypertensive rat experiment, find that tentatively this compound has certain antihypertensive effect.
Description of drawings
Fig. 1 is 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
1The HNMR spectrogram;
Fig. 2 is 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
13C NMR spectrogram;
Fig. 3 is 2-normal-butyl-3-{[2 '-carboxyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1, the mass spectrum of 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone.
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.
Embodiment 1 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 (1)
Step 1: Synthetic 2 '-methoxycarbonyl-4 '-fluoro-4-methyl diphenyl
Adding 4-methylphenylboronic acid in the 250ml reaction flask (5g, 25mmol), 2-bromo-5-fluorophenyl carbamate (7.0g, 30mmol), excessive K
2CO
3(17.3g, 0.175mol), Ph
3P (4.8g, 0.018mol) and Pd (OAC)
2(2.8g, 0.013mol), add volume ratio simultaneously and be 4: 11, the mixed solvent 150ml of 4-dioxane and distilled water.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), 2 '-methoxycarbonyl-4 '-fluoro-4-methyl diphenyl
5.0g, productive rate 82.60%.
Step 2: synthetic 4 '-fluoro-4-methyl diphenyl-2 '-formic acid
Add compound 2 '-methoxycarbonyl-4 '-fluoro-4-methyl diphenyl (2.69g in the 50ml reaction flask, 11mmol), and sodium hydroxide (1.32g, 33mmol), methyl alcohol 20ml, distilled water 10ml, 60 ℃ of reflux were spin-dried for methyl alcohol after 5 hours, water extracted with diethyl ether three times, discard organic phase, it is the neutralization of 2%～4% dilute hydrochloric acid that water adds massfraction, and the adularescent material is separated out.Dry behind the suction filtration solid
1.69g, productive rate 66.62%.
The collection of illustrative plates of 4 '-fluoro-4-methyl diphenyl-2 '-formic acid, as follows:
1HNMR(400MHz，CDCl
3)δ：7.67～7.12(m，7H，Ph-H)，2.42(s，3H，Ph-CH
3)；MS(ESI)m/z：229.1[M-H]
-。
Step 3: Synthetic 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-methyl diphenyl
Add in the 50ml reaction flask 4 '-fluoro-4-methyl diphenyl-2 '-formic acid (1.88g, 8.17mmol) and CH
2Cl
2Dropping oxalyl chloride under the 15ml, ice bath (0.86ml, 10mmol), stirring at room 3 hours is spin-dried for reaction solution, adds anhydrous THF 20ml, ice bath drips potassium tert.-butoxide (0.92g down, 8.19mmol), dropwised the back stirring at room 1 hour, reaction solution is poured in the frozen water, ethyl acetate extraction, collect organic phase, drying, (eluent is a sherwood oil to the silica gel H column chromatography for separation: ethyl acetate=120: 1～150: 1) get product
1.04g, productive rate 44.22%.
The collection of illustrative plates of 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-methyl diphenyl, as follows:
1HNMR(400MHz，CDCl
3)δ：7.50-7.27(m，7H，Ph)，2.46(s，3H，Ph
CH 3 )，1.32(s，9H，PhCOO
C 4 H 9 )；
13CNMR(400MHz，CDCl
3)δ：169.09，169.07，167.73，162.63，140.56，140.52，140.29，139.13，137.00，136.94，135.76，135.67，134.65，134.57，131.05，130.90，124.28，124.03，119.90，119.69，118.81，118.58，116.91，116.70，84.01，54.70，29.89，23.43。
Step 4: Synthetic 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-bromomethylbiphenyl
Add in the 50ml reaction flask 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-methyl diphenyl (1g, 3.5mmol), NBS (0.68g, 3.8mmol), AIBN (86mg, 0.52mmol), hexanaphthene 20ml, 75～85 ℃ of reflux 3～4 hours are after reacting completely, cooling, suction filtration, the solid washed with dichloromethane is collected organic phase, (eluent is a sherwood oil: ethyl acetate=150: 1～200: 1), get product to be spin-dried for back silica gel H column chromatography for separation
0.84g, productive rate 65.79%.
The collection of illustrative plates of 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-bromomethylbiphenyl, as follows:
1HNMR(400MHz，CDCl
3)δ：7.52(dd，1H，J
1＝9.2Hz，J
2＝2.8Hz，Ph)，7.43(d，2H，J＝4.4Hz，Ph)，7.23～7.31(m，3H，Ph)，7.15～7.22(m，1H，Ph)，4.57(s，2H，Ph
CH 2 )，1.25(s，9H，CH
3)；
13CNMR(400MHz，CDCl
3)δ：168.78，165.36，162.89，143.52，139.86，139.83，139.18，136.97，136.89，134.52，134.44，131.43，131.24，131.09，131.04，120.13，119.92，119.12，118.89，84.39，35.55，32.03，29.90。
Step 5: Synthetic 2-normal-butyl-3-{[2 '-tertbutyloxycarbonyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone
Add 2-normal-butyl-1 in the 50ml reaction flask; 3-diazaspiracyclic (4; 4) ninth of the ten Heavenly Stems-1-alkene-4-ketone (0.58g; 2.63mmol); mass concentration is 60% sodium hydride (0.25g; 6.25mmol); nitrogen protection adds anhydrous THF 15ml down, and 50 ℃ are stirred half an hour, and the cooling back drips 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-bromomethylbiphenyl (0.80g; 2.2mmol) THF20～25mL drips of solution finish; continue reaction after 3 hours, reaction solution is poured in the frozen water into ethyl acetate extraction; collect organic phase, (eluent is a sherwood oil to dry back silica gel H column chromatography for separation: ethyl acetate=4: 1～2: 1) get product
0.33g, productive rate 30.65%.
2-normal-butyl-3-{[2 '-tertbutyloxycarbonyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1, the collection of illustrative plates of 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, as follows:
1HNMR(400MHz，CDCl
3)δ：7.47(dd，1H，J
1＝9.2Hz，J
2＝2.8Hz，Ph)，7.14～7.27(m，6H，Ph)，4.72(s，2H，Ph
CH 2 )，2.35(t，2H，J＝7.6Hz，-C
H 2CH
2CH
2CH
3)，2.01～1.79(m，8H，CH
2CH
2CH
2CH
2)，1.61(quint，2H，J＝7.6Hz，-CH
2C
H 2CH
2CH
3)，1.35(sext，2H，J＝7.6Hz，-CH
2CH
2C
H 2CH
3)，1.25(s，9H，3CH
3)，0.89(t，3H，J＝7.6Hz，-CH
2CH
2CH
2C
H 3)；
MS(ESI)m/z：479.2[M+H]
+。
Step 6: Synthetic 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
Add 2-normal-butyl-3-{[2 '-tertbutyloxycarbonyl-4 '-fluorine (1,1-biphenyl)-4-yl in the 50ml reaction flask] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone (0.30g, 0.63mmol), 2ml CF
3COOH, the 2ml methylene dichloride, stirring at room 2 hours removes solvent under reduced pressure, adds ether, and visible white crystal is separated out, and the suction filtration after drying gets product
0.26g, productive rate 99.3%.
2-normal-butyl-3-{[2 '-carboxyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1, the collection of illustrative plates of 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, as follows:
1HNMR(400MHz，DMSO)δ：9.08(s，1H，PhCOOH)，7.66(dd，1H，J
1＝8.8Hz，J
2＝2.8Hz，Ph)，7.23～7.33(m，6H，Ph)，4.81(s，2H，Ph
CH 2 )，2.67(t，2H，J＝7.6Hz，C
H 2CH
2CH
2CH
3)，1.99～2.15(m，8H，CH
2CH
2CH
2CH
2)，1.56(quint，2H，J＝7.6Hz，CH
2C
H 2CH
2CH
3)，1.29(sext，2H，J＝7.6Hz，CH
2CH
2C
H 2CH
3)，0.86(t，3H，J＝7.6Hz，N＝CCH
2CH
2CH
2C
H 3)；
13CNMR(400MHz，DMSO)δ：170.91，164.99，162.55，161.23，142.10，139.59，137.47，136.92，135.46，131.63，129.33，120.66，120.45，118.67，118.44，76.09，45.82，39.55，30.08，29.12，28.08，24.24，16.21；
MS(ESI)m/z：423.1[M+H]
+。
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 I)
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 | 45.55±10.33 ** | 45.52±13.51 **## | 16.01±5.34# |
Annotate: compare with the blank group:
*P＜0.01; Compare with positive controls: #P＜0.05, ##P＜0.01.
Claims (8)
1. the assorted spirocyclic ketone compound of 2 '-carboxyl-4 '-fluorine biphenyl, it is characterized in that: this compound is 2-normal-butyl-3-{[2 '-carboxyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1, in 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, its structure is:
Its fusing point is 158～160 ℃.
2. 2-normal-butyl-3-{[2 '-carboxyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1, the preparation method of 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone may further comprise the steps:
1) Synthetic 2 '-methoxycarbonyl-4 '-fluoro-4-methyl diphenyl
Add 25～30mmol4-methylphenylboronic acid, 30～35mmol2-bromo-5-fluorophenyl carbamate and excessive K in the reaction flask
2CO
3, the Ph of catalytic amount
3P and Pd (OAC)
2, add 140～150mL volume ratio simultaneously and be 4: 11, the mixed solvent of 4-dioxane and water, 95～110 ℃ of reflux 1.5～2.5 hours are separated organic phase, concentrate the back column chromatography for separation, 2 '-methoxycarbonyl-4 '-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;
2) synthetic 4 '-fluoro-4-methyl diphenyl-2 '-formic acid
Add 10～12mmol2 '-methoxycarbonyl-4 '-fluoro-4-methyl diphenyl, 30～35mmol sodium hydroxide, methyl alcohol 20～30mL, water 10～15mL in the reaction flask, 55～65 ℃ of reflux are after 4.5～5.5 hours, be spin-dried for methyl alcohol, the water extracted with diethyl ether, discard organic phase, water adds the dilute hydrochloric acid neutralization, gets 4 '-fluoro-4-methyl diphenyl-2 '-formic acid;
3) Synthetic 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-methyl diphenyl
The CH that adds 4 ' of 8.0～8.5mmol-fluoro-4-methyl diphenyl-2 '-formic acid and 15～20mL in the reaction flask
2Cl
2Ice bath drips 10～12mmoL oxalyl chloride down, and stirring at room 3～4 hours is spin-dried for reaction solution, add 20～25mL anhydrous tetrahydro furan, ice bath drips 8.0～8.5mmol potassium tert.-butoxide down, dropwises the back stirring at room 1～2 hour, and reaction solution is poured in the frozen water, ethyl acetate extraction, collect organic phase, drying, column chromatography for separation gets product;
4) Synthetic 2 '-tertbutyloxycarbonyl-4 '-fluoro-4-bromomethylbiphenyl
Add 2 ' of 3.5～4.0mmol-tertbutyloxycarbonyl-4 '-fluoro-4-methyl diphenyl, 3.8～4.2mmol N-bromo-succinimide, 0.50～0.55mmol Diisopropyl azodicarboxylate, 20～30mL hexanaphthene in the reaction flask, after the reaction in 3～4 hours of 75～85 ℃ of reflux, cooling, suction filtration, the solid washed with dichloromethane, collect organic phase, be spin-dried for the back column chromatography for separation;
5) Synthetic 2-normal-butyl-3-{[2 '-tertbutyloxycarbonyl-4 '-fluorine (1,1-biphenyl)-4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone
Under the nitrogen protection, 2.6 the 2-normal-butyl-1 of～2.7mmol, 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, mass concentration are 60% sodium hydride 6～7mmol, anhydrous tetrahydro furan 10～20mL, 45～55 ℃ were stirred 0.5～1 hour, the cooling back drips the tetrahydrofuran solution 20～25mL of 0.09～0.11mol/L2 '-tertbutyloxycarbonyl-4 '-fluoro-4-bromomethylbiphenyl, drip and finish, continue reaction after 2.5～3.5 hours, reaction solution is poured in the frozen water, ethyl acetate extraction is collected organic phase, dry back column chromatography for separation;
6) Synthetic 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
2-normal-butyl-3-{[2 '-tertbutyloxycarbonyl-4 '-fluorine (1,1-the biphenyl)-4-yl that adds 0.6～0.7mmol in the reaction flask] methyl } 1, the CF of 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, 1～2mL
3The methylene dichloride of COOH, 2～4mL, stirring at room 1.5～2.5 hours is removed and to be desolvated, and adds ether, 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.
3. a kind of 2-normal-butyl-3-{[2 ' according to claim 2-carboxyl-4 '-fluorine (1,1-biphenyl)-and the 4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-preparation method of 1-alkene-4-ketone, it is characterized in that: in the described step 1), 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.
4. a kind of 2-normal-butyl-3-{[2 ' according to claim 2-carboxyl-4 '-fluorine (1,1-biphenyl)-and the 4-yl] methyl } 1, the preparation method of 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone, it is characterized in that: described step 2), the mass concentration of dilute hydrochloric acid is 2%～4%.
5. a kind of 2-normal-butyl-3-{[2 ' according to claim 2-carboxyl-4 '-fluorine (1,1-biphenyl)-and the 4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-preparation method of 1-alkene-4-ketone, it is characterized in that: in the described step 3), 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 120: 1～150: 1.
6. a kind of 2-normal-butyl-3-{[2 ' according to claim 2-carboxyl 4 '-fluorine (1,1-biphenyl)-and the 4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-preparation method of 1-alkene-4-ketone, it is characterized in that: in the described step 4), 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: 1～200: 1.
7. a kind of 2-normal-butyl-3-{[2 ' according to claim 2-carboxyl-4 '-fluorine (1,1-biphenyl)-and the 4-yl] methyl } 1,3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-preparation method of 1-alkene-4-ketone, it is characterized in that: in the described step 5), 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 4: 1～2: 1.
8.2-normal-butyl-3-{[2 '-carboxyl-4 '-fluorine (1,1-biphenyl)-and the 4-yl] methyl } 1, the application of 3-diazaspiracyclic (4,4) ninth of the ten Heavenly Stems-1-alkene-4-ketone in the medicine of preparation prevention or treatment hypertension, coronary heart disease, heart brain and kidney blood vessel diseases and pulmonary hypertension disease.
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| WO1993004046A1 (en) * | 1991-08-19 | 1993-03-04 | E.I. Du Pont De Nemours And Company | Angiotensin ii receptor blocking imidazolinone derivatives |
| WO1994001436A1 (en) * | 1992-07-10 | 1994-01-20 | The Boots Company Plc | Dioxcyclobutene derivatives as angiotensin ii antagonists |
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| WO1993004046A1 (en) * | 1991-08-19 | 1993-03-04 | E.I. Du Pont De Nemours And Company | Angiotensin ii receptor blocking imidazolinone derivatives |
| WO1994001436A1 (en) * | 1992-07-10 | 1994-01-20 | The Boots Company Plc | Dioxcyclobutene derivatives as angiotensin ii antagonists |
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