CN102816126A - Sulfamoyl-aryl-substituted triazole derivatives with cardiovascular activity, preparation method thereof, and application thereof - Google Patents
Sulfamoyl-aryl-substituted triazole derivatives with cardiovascular activity, preparation method thereof, and application thereof Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, and specifically relates to a preparation method of sulfamoyl-aryl-substituted triazole derivatives with cardiovascular activity. According to the invention, R1, R2, R3, and R4 are defined as in the specifications. The invention also relates to medical applications of the derivatives, especially the applications of the derivatives as medicines used for resisting hypertension and having cardiovascular protective effects.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field; The substituted triazole class verivate of amine sulphonyl aryl that to be specifically related to one type of biphenyl be skeleton, pharmaceutical composition and the said compound that the invention also discloses the preparation method of this analog derivative and contain said compound is in treatment hypertension, congestive heart failure and through exciting Angiotensin II (AT
2) acceptor treats the application in other disease or the illness.
Background technology
RAS (RAS) plays an important role in blood pressure regulation and body fluid, electrolyte balance.(angiotensinII is a kind of important multi-functional vaso-active substance among the RAS AngII) to Angiotensin II, has confirmed that Ang II is directly through two kinds of different receptor subtype AT in the human body
1And AT
2Acceptor plays a role.AT
1Receptor-mediated most physiological functions are like vasoconstriction, increase water-sodium retention etc.AngII and AT
2(nitric oxide NO)/the cGMP cascade reaction, produces cardiovascular provide protection to activate kallidin-9/nitrogen protoxide after the receptors bind.
II Angiotensin II AT
1Receptor antagonist exposes some untoward reactions gradually in lots of clinical is used, but such medicine is still antihypertensive drug and the anti-heart failure medicine that has than the big market potentiality.AT
2Receptor stimulant is known as " AT
1The acceptor natural agonist ", AT
1Receptor antagonist and AT
1After the receptors bind, promote AngII and AT
2Receptors bind activates AT
2Acceptor.AT
2Acceptor more and more receives publicity as a potential drug target.Research shows II Angiotensin II AT
2Receptor stimulant can improve the whole structure of hypertension therapeutic, improves health level, and such medicine might become II Angiotensin II AT
1The natural partner of receptor antagonist is called as the depressor of New Times.
This seminar basis is both at home and abroad to selectivity AT
2The latest report of receptor stimulant
[1-5]In conjunction with existing structure activity relationship information; Selection is basic framework with biphenyl, and parent heterocycle structure and substituting group thereof are carried out structure of modification, and design has been synthesized a series of new substituted triazole class verivates of amine sulphonyl aryl (referring to 1.Carey R M.Current Opinion inNephrology & Hypertension; 2005,14 (1): 67-71; 2.Wan Y, Wallinder C, Plouffe B, et al.JMed Chem, 2004,47 (24): 5995-6008; 3.Wu X, Wan Y, Mahalingam A K, et al.J MedChem, 2006,49 (24): 7160-7168; 4.Murugaiah A M S, Wallinder C, Mahalingam A K, et al.Bioorg Med Chem, 2007,15 (22): 7166-7183; 5.Wallinder C, Botros M,
U, et al.Bioorg Med Chem, 2008,16 (14): 6841-6849.).
Summary of the invention
The AT that has the selectivity cardiac vascular activity for searching
2The receptor stimulant kind new medicine; The present invention found substituting group 4 '-[1-(3-replacement-1H-1; 2, the 4-triazole) methyl]-5-substituted biphenyl-2-sulfoamido carboxylicesters or N-4 '-[1-(3-replacement-1H-1,2; The 4-triazole) methyl]-new compound of 5-isobutyl-biphenyl-2-alkylsulfonyl alkylamide class formation, thus a series of verivates with general formula (I) structural performance are provided.General formula (I) has been expanded existing AT
2The constitutional features of receptor stimulant medicine and range of structures.
The technical problem that the present invention will solve is the AT that has of research new texture type
2The compound of receptor agonist activity, and a kind of pharmaceutical composition of treating hypertension, congestive heart failure and other disease or illness further is provided.Another object of the present invention provides above-mentioned medicinal compsns and passes through exciting AT in preparation
2Acceptor is treated the purposes of the medicine aspect of other disease or illness.
For solving the problems of the technologies described above, the present invention provides following technical scheme:
The compound or pharmaceutically acceptable salt thereof of general formula (I):
R wherein
1Represent hydrogen, alkoxyl group, carboxyl, carbalkoxy, ester group;
R
2Represent hydrogen, C
1-C
6The alkyl of straight or branched, C
2-C
6The alkenyl of straight or branched, C
2-C
6The alkynyl of straight or branched, C
1-C
6The alkoxyl group of straight or branched, phenyl, fragrant heterocycle perhaps replace fragrant heterocycle, and said replacement heterocyclic base can be chosen wantonly from one or more C of being selected from
1-C
6Alkyl, C
1-C
6Alkoxy or halogen replaces, and each substituting group is identical or different;
R
3Represent hydrogen, C
1-C
4Alkyl or halogen;
R
4Represent hydrogen, C
1-C
4Alkyl or alkoxyl group;
Ar represents phenyl or fragrant heterocycle, and said fragrant heterocycle refers to 1-2 the fragrant heterocycle of heteroatomic 5-6 unit, and said heteroatoms independently is selected from O, S or N separately.
What the compound or pharmaceutically acceptable salt thereof of general formula (I) was even more ideal is: R wherein
1Be hydrogen, carbalkoxy or ester group; R
2Be C
1-C
4Straight chained alkyl or C
1-C
4The straight chain alkoxyl group; R
3Represent hydrogen or halogen, R
4Represent hydrogen; Ar represents phenyl ring, pyrroles or thiphene ring.
The present invention includes a kind of Mammals that is used to treat, be preferable over the pharmaceutical composition of treatment human diseases or illness, it comprises treatment hypertension, congestive heart failure, myocardial hypertrophy, vasospasm and passes through exciting AT
2Acceptor is treated compound or its salt and pharmaceutically acceptable carrier of the general formula (I) of the significant quantity of other disease or illness.
The present invention comprises that also the compound or its salt of general formula (I) is preparing treatment hypertension, congestive heart failure, myocardial hypertrophy, vasospasm and passing through exciting AT
2Acceptor is treated the application in the medicine of other illness.
Reaction 1
Reaction 2
Reaction 3
Reaction 4
With reference to reaction scheme 1, substituted 1,2,4-triazole (1) and bromine bromobenzyl (2) mixed, in the alkaline medium, preferred salt of wormwood, backflow 12h, through filtering, acidifying, preferred hydrochloric acid filters, and solid chemical compound alkalizes again, makes corresponding formula (3) compound.
With reference to reaction scheme 2, formula (4) compound is added in the chloroform, drip chlorsulfonic acid in 0-5 ℃ and react, after dripping; In room temperature refluxed 3-5h, reaction solution is slowly added in the trash ice, layering, water layer is used ethyl acetate extraction; Make corresponding formula (5) compound, formula (5) compound is dissolved in the methylene dichloride, add triethylamine; Drip TERTIARY BUTYL AMINE, room temperature reaction 8-12h makes corresponding formula (6) compound.
Formula (6) compound is dissolved in the THF, in below-78 ℃, drips n-Butyl Lithium ,-20 ℃ are stirred 12-18h, add acid, get corresponding formula (7) compound.
With formula (3) compound and formula (7) compound and toluene, mix in the ethanol, add palladium, triphenylphosphine, in basic soln, backflow 5-6h adds water, continues reaction 3-5h, gets corresponding formula (8) compound.
Formula (8) compound is dissolved in the methylene dichloride, adds trifluoracetic acid, react 12h under the room temperature, get formula (9) compound.
Formula (9) compound is dissolved in the methylene dichloride, and adding formula (10) compound reacts 1-3h under the room temperature, gets formula (I) title product.
Below be the pharmacology test and the data of part of compounds of the present invention, the structure that the compound code name is corresponding in the pharmacological testing is seen embodiment.
On preliminary basis, select sample embodiment 12,13 and further study as the trial-product group to the prerun of trial-product group; With male spontaneous hypertensive rat (SHR) sample is screened, every treated animal quantity is 8.
Blank group (giving equivalent saline water);
Each treated animal adopts oral administration, and dosage is 20mg/kg, and the medicine liquid irrigation stomach is preceding with 37 ℃ of water temperature heat, administration volume 0.8ml/100g.
Blood pressure (SAP, DAP, MAP) and heart rate (HR) result that each treated animal is measured all represent with
± s, carries out (pairing) before and after the self administration and reach and the t-test statistics processing of blank group between organizing.
The acute reduced pressure experiment of 12,13 pairs of anesthesia of compound SHR rat
Annotate: 1.*:P＜0.1; *: P＜0.05; Compare with control group * *: P＜0.01.
2. blood pressure (heart rate) before blood pressure (heart rate)-administration after blood pressure (heart rate) absolute change value (Δ)=administration
The result finds that compound 12 has tangible hypotensive effect suitable with the positive drug losartan; Compound 13 has hypotensive activity preferably, and its antihypertensive effect is near the positive drug losartan, and the two compares difference to the heart rate of anesthesia SHR with control group do not have significance meaning (P＞0105), has further researching value.
Embodiment
Embodiment 1
1-(4-bromobenzyl)-1H-1,2, the 4-triazole
With triazole (2.011g, 0.029mol), (1.022g 7.341mmol) joins in the eggplant-shape bottle of 50ml salt of wormwood successively, adds solvent THF (30ml); Stir 10min, (3.691g 0.015mol) is dissolved among the DMF (5ml), is added dropwise in the reaction solution to the bromine bromobenzyl; Be warming up to backflow after dropwising, react about 15h, suction filtration, concentrating under reduced pressure; Add 15ml water, the adularescent solid is separated out, and suction filtration gets white solid 2.374g, yield: 68.9%.
1HNMR(CDCl
3，300MHz)：δ(ppm)5.307(2H，s，CH
2)，7.144(each?1H，d，J＝8.4Hz，CH
2-Ar)，7.511(each?1H，d，J＝8.4Hz，CH
2-Ar)，7.498(1H，s，3H)，8.098(1H，s，4H)；EI-MS，m/z：237，M：[M+2]＝1∶1.
Embodiment 2
4-isobutyl-benzene SULPHURYL CHLORIDE
(3.421g 0.0255mol) is dissolved in imitative chlorine (30ml), drops in the three-necked bottle of 100ml with isobutyl-benzene; After under cryosel is bathed, stirring 10min, (11.815g 0.102mol) is added dropwise in the reaction flask chlorsulfonic acid; Drip off in the 45-60min, the dropping process keeps temperature to be no more than 5 ℃.At room temperature react 45min after dripping.Reaction solution is poured in the trash ice, and standing demix takes out organic layer, and water layer is used CH
2Cl
2Extraction (20ml * 2) merges organic layer, saturated NaHCO
3Solution is washed (30ml * 2), saturated nacl aqueous solution washing organic layer (30ml * 2), anhydrous MgSO
4Drying, suction filtration, filtrate decompression concentrate faint yellow oily thing (42) 2.264g, yield: 38.2%.
Embodiment 3
The N-tertiary butyl-4-isobutyl-benzene sulphonamide
(3.232g 0.0139mol) adds in the eggplant-shape bottle of 50ml, adds CH with 4-isobutyl-benzene SULPHURYL CHLORIDE
2Cl
2(30ml), triethylamine (1.547g, 0.0153mol), stir 10min after, begin to drip TERTIARY BUTYL AMINE (1.220g, 0.0167mol).Behind the reaction 8h, suction filtration is filtrated and is washed (25ml * 3) under the room temperature, saturated nacl aqueous solution washing organic layer (30ml * 2), anhydrous Na S0
4Dried overnight, suction filtration, filtrate decompression concentrate 3.157g white solid (43), yield: 79.0%.
Embodiment 4
2-(N-tertiary butyl sulfamyl)-5-isobutyl-benzene boric acid
The N-tertiary butyl-4-isobutyl-benzene sulphonamide is joined in the three-necked bottle of 150ml, add anhydrous THF (35ml), vacuumize N in the bottle
2Protection.The external application liquid nitrogen cooling is to-78 ℃, begin to drip n-Butyl Lithium (2.5M/L, 0.0293mol); Temperature maintenance is at-80 ℃～-75 ℃ in the dropping process; Dropwise the back holding temperature at-20 ℃ of reaction 4h, be cooled to-78 ℃, drip triisopropyl borate ester (3.301g; 0.0176mol), rise to room temperature reaction and spend the night.Add 2M HCl and be slightly acidic to reaction solution, standing demix, organic layer is continued to employ, and water layer merges organic layer with EtOAc extraction (20ml * 2), concentrating under reduced pressure, column chromatography (sherwood oil: ETHYLE ACETATE=5: 1) get faint yellow oily thing 2.060g, yield: 56.3%.
1HNMR(CDCl
3，300MHz)：δ(ppm)0.863(6H，d，J＝6.6Hz)，1.079(9H，s，t-Bu)，1.858(1H，m，CH)，6.825(1H，s，NH)，7.271(1H，d，J＝4.2Hz，H-4)，7.381(1H，s，H-6)，7.721(1H，d，J＝7.8Hz，H-3)，8.356(2H，s，B(OH)
2).
Embodiment 5
4 '-[(1H-1,2,4-triazole-1-yl) the methyl]-N-tertiary butyl-5-isobutyl--2-biphenyl sulphonyl ammonia
In the 100ml three-necked bottle, add 2-(N-tertiary butyl sulfamyl)-4-isobutyl-benzene ylboronic acid (0.799g, 2.55mmol), 1-(4-bromobenzyl)-1H-1,2, the 4-triazole (0.620g, 2.55mmol); Toluene (15ml), and NaOH (1.56M, 7ml), ethanol (12ml), the adding palladium (14mg, 0.05mmol); Triphenylphosphine (55mg, 0.204mmol), logical nitrogen protection, reflux 5h, stopped reaction; Remove nitrogen, be cooled to room temperature, add water 20ml standing demix, organic layer is continued to employ, and water layer uses ETHYLE ACETATE (20ml * 3) to extract again; Merge organic layer, saturated nacl aqueous solution washing organic layer, anhydrous magnesium sulfate drying concentrates column chromatography (CH
2Cl
2: CH
3OH=80: 1) get faint yellow oily thing 0.940g, yield: 86.6%.
1HNMR(CDCl
3，300MHz)：δ(ppm)0.905(6H，d，J＝6.6Hz)，0.987(9H，s)，1.897(1H，m)，2.535(2H，d，J＝7.2Hz)，3.515(1H，s，NH)，7.048(1H，d，J＝1.5Hz，H-4)，7.238(1H，d，J＝0.9Hz，H-6)，7.343(each?1H，d，J＝4.2Hz，CH
2-Ar)，7.529(each?1H，d，J＝8.1Hz，CH
2-Ar)，7.995(1H，s，3H)，8.051(1H，d，J＝8.1Hz，H-3)，8.149(1H，s，4H).
Embodiment 6
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-isobutyl--2-sulphonyl ammonia
With 4 '-[1-(1H-1,2,4-triazole) the methyl]-N-tertiary butyl-5-isobutyl--2-sulfamyl biphenyl (1.130g; 0.00265mol) join in the 25ml eggplant-shape bottle, add TFA (4ml), stir; After reacting 12h under the room temperature; Concentrating under reduced pressure is removed most of TFA, ETHYLE ACETATE (15ml) dissolving, saturated NaHCO
3The washing organic layer, anhydrous Na SO
4Dried overnight, suction filtration, filtrate decompression concentrates, column chromatography (CH
2Cl
2: CH
3OH=80: 1) get faint yellow solid 0.536g, yield: 54.6%.
ESI-MS，m/z：369[(M-H)
-]，371[(M+H)
+].
Embodiment 7
N-{4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-isobutyl-biphenyl-2-alkylsulfonyl } propionic acid amide
With 4 '-[1-(1H-1,2,4-triazole) methyl]-(0.197g 0.510mmol) joins in the 25ml eggplant-shape bottle 5-isobutyl--2-biphenyl sulfonamide, adds anhydrous CHCl
3(4ml), add triethylamine (0.1ml), ice bath adds propionyl chloride (0.1ml) after stirring 10min down, under the room temperature behind the reaction 3h, and concentrating under reduced pressure, column chromatography (CH
2Cl
2: CH
3OH=80: 1) get white solid 62.7mg.Productive rate: 28.9%.mp?144-146℃。
IR(film，cm
-1)：2957，2926，2024，1704，1467，1333，1141；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.818(6H，d，J＝5.1Hz，(
CH 3)
2CH)，0.905(3H，t，J＝5.1Hz，CH
3)，2.008(2H，q，J＝7.5，15Hz，CH
2)，1.830～1.972(1H，m，(CH
3)
2 CH)，2.542(2H，d，J＝6.9Hz，
CH 2CH)，5.438(s，2H，CH
2)，7.039(1H，d，J＝1.2Hz)，7.337(4H，dd，J＝3.9，2.7Hz)，7.998(1H，s)，8.195(2H，d，J＝8.1Hz)，8.292(1H，s)；
ESI-MS，m/z：425[(M-H)
-]，427[(M+H)
+].
Embodiment 8
N-{4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-isobutyl-biphenyl-2-alkylsulfonyl } valeramide
Preparing method with reference to embodiment 7.Productive rate: 31.5%.mp?100-102℃。
IR(film，cm
-1)：3439，2957，2024，1717，1336，1138；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.885(3H，t，J＝6.9Hz，CH
3)，0.942(6H，d，J＝6.6Hz，(
CH 3)
2CH)，1.452～1.477(m，2H，CH
3 CH 2)，1.879～1.961(4H，m)，1.187～1.211(1H，m，(CH
3)
2 CH)，2.539(2H，d，J＝6.0Hz，CH
2CO)，5.435(2H，s)，7.038(1H，s)，7.232～7.358(m，5H)，7.965(1H，s)，8.199(1H，dd，J＝1.5，6.6Hz)，8.248(1H，s)；
ESI-MS，m/z：453.3[(M-H)
-]，455[(M+H)
+].
Embodiment 9
N-{4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-isobutyl-biphenyl-2-alkylsulfonyl }-the 4-monomethylaniline
With 4 '-[(1H-1,2,4-triazole-1-yl) methyl]-(0.197g 0.510mmol) joins in the 25ml eggplant-shape bottle 5-isobutyl--2-sulphonyl ammonia, adds anhydrous CHCl
3(4ml), add triethylamine (0.1ml), after ice bath stirs 10min down, homemade Tosyl chloride is added dropwise to is dissolved in anhydrous CHCl
3Be added dropwise in the reaction flask, under the room temperature reaction 3h after, concentrating under reduced pressure, column chromatography (CH
2Cl
2: CH
3OH=80: 1) get white solid 30mg.Productive rate: 12.1%.mp?100～102℃。
IR(film，cm
-1)：3438，2956，2024，1752，1607，1228，1163；ESI-MS，m/z：487.2[(M-H)
-].
Embodiment 10
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-isobutyl-biphenyl-2-sulfoamido ethyl formate
With 4 '-[(1H-1,2,4-triazole-1-yl) methyl]-(0.311g 0.807mmol) is dissolved in anhydrous pyridine (4ml) to 5-isobutyl--2-sulphonyl ammonia; After ice bath stirs 10min down, and the adding Vinyl chloroformate (0.193ml, 2.021mmol), after ice bath reacts 4h down; Add water, ethyl acetate extraction merges organic layer; 1M HCl washs organic layer (20ml * 3), and saturated nacl aqueous solution is washed, column chromatography (CH
2Cl
2: CH
3OH=80: 1) get white solid 0.197g.Productive rate: 55.2%.mp96-98℃。
IR(film，cm
-1)：3415，2957，2025，1744，1340，1161，1144，576；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.844(6H，d，J＝6.6Hz，(
CH 3)
2CH)，1.064(3H，t，J＝6.9Hz，
CH 3CH
2)，1.785～1.874(1H，m，(CH
3)
2 CH)，2.476(2H，d，J＝7.2Hz，CH
2 CH)，4.014(2H，q，J＝7.2，7.2Hz，
CH 2CH
3)，5.300(2H，s，
CH 2CH)，6.978(1H，d，J＝1.5Hz)，7.148(2H，d，J＝8.1Hz)，7.240～7.288(m，3H)，7.853(1H，s)，8.039(s，1H)，8.103(1H，d，J＝8.1Hz)，8.473(1H，s)；ESI-MS，m/z：442[(M-H)
-].
Embodiment 11
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-base biphenyl-2-sulfoamido t-butyl formate
With 4 '-[(1H-1,2,4-triazole-1-yl) methyl]-(0.180g 0.486mmol) is dissolved in anhydrous CH to 5-isobutyl--2-sulphonyl ammonia
2Cl
2(4ml), add triethylamine (0.1ml), ice bath adds (Boc) after stirring 10min down
2O (0.127g, 0.584mmol), under the room temperature reaction 6h after, concentrating under reduced pressure, column chromatography (CH
2Cl
2: CH
3OH=80: 1) get white solid 0.103g.Productive rate: 45.2%.mp?97-100℃。
IR(film，cm
-1)：3418，2958，2925，2024，1739，1515，1341，1139；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.844(6H，d，J＝6.6Hz)，1.229(9H，s，t-Bu)，1.773～1.811(m，1H)，2.486(2H，d，J＝7.2Hz)，5.330(2H，s)，6.993(1H，s)，1.171(1H，s)，7.199(2H，d，J＝2.4Hz)，7.273(1H，d，J＝3.0Hz)，7.315(2H，d，J＝6.3Hz)，7.892(1H，s)，8.058(1H，s)，8.084(1H，s)；ESI-MS，m/z：469.3[(M-H)
-].
Embodiment 12
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-isobutyl-biphenyl-2-sulfoamido butyl formate
Preparing method with reference to embodiment 10.Yield: 40.9%.mp?78-80℃。
IR(film，cm
-1)：3417，2958，2930，2024，1743，1510，1342，1160，1144；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.767(3H，t，J＝7.5Hz，CH
3)，0.842(6H，d，J＝6.6Hz)，1.335～1.350(2H，m，CH
3 CH 2)，1.809～2.022(1H，m)，2.480(2H，d，J＝7.2Hz，
CH 2CH)，3.948(2H，t，J＝6.6Hz，CH
2O)，5.342(s，2H)，6.993(1H，d，J＝1.5Hz)，7.117(1H，s)，7.217～7.299(5H，m)，7.918(1H，s)，8.074(1H，s)，8.095(1H，d，J＝3.6Hz)；
ESI-MS，m/z：469.3[(M-H)
-].
Embodiment 13
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-isobutyl-biphenyl-2-sulfoamido benzyl formate
Preparing method with reference to embodiment 10.Yield: 31.1%.mp?100-102℃。
IR(film，cm
-1)：3419，3033，2957，2926，2025，1745，1510，1342，1160，1144；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.895(2H，d，J＝8.4Hz)，1.854～1.944(m，1H)，2.546(2H，d，J＝7.2Hz)，5.022(2H，s，CH
2O)，5.327(2H，s，CH
2)，6.998(1H，s)，7.111～7.198(m，5H)，7.307～7.328(m，3H)，7.730(1H，s)，8.126(1H，s)，8.166(2H，d，J＝7.5Hz)；
ESI-MS，m/z：503[(M-H)
-].
Embodiment 14
4-isobutyl-benzene SULPHURYL CHLORIDE
With reference to the preparation method of embodiment 2, get faint yellow oily thing, yield: 42.0%.
Embodiment 15
The N-tertiary butyl-4-isobutyl-benzene sulphonamide
With reference to the preparation method of embodiment 3, get white solid, yield: 83.5%.
Embodiment 16
2-(N-tertiary butyl sulfamyl)-5-methoxyphenylboronic acid
With reference to the preparation method of embodiment 4, get faint yellow oily thing, yield: 56.1%.
1HNMR(CDCl
3，300MHz)：δ(ppm)1.184(9H，s)，3.384(3H，s，CH
3O)，4.675(1H，s，NH)，5.963(2H，s，B(OH)
2)，6.960(1H，d，J＝6.3Hz，H-4)，7.368(1H，s，H-6)，7.970(1H，d，J＝10.5Hz，H-3).
Embodiment 17
4 '-[1-(1H-1,2,4-triazole-1-yl) the methyl]-N-tertiary butyl-5-methoxyl group-2-biphenyl sulphonyl ammonia
With reference to the preparation method of embodiment 5, get faint yellow oily thing, yield: 76.2%.
1HNMR(CDCl
3，300MHz)：δ(ppm)0.996(9H，s，t-Bu)，3.450(1H，s，NH)，3.862(3H，s，CH
3O)，6.766(1H，d，J＝2.7Hz，H-4)，6.944(1H，d，J＝9.0Hz，H-6)，7.335(each?1H，d，J＝8.1Hz，CH
2-Ar)，7.525(each?1H，d，J＝7.8Hz，CH
2-Ar)，7.997(1H，s，3H)，8.085(1H，d，J＝8.7Hz，H-3)，8.150(1H，s，4H).
Embodiment 18
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-methoxyl group-2-biphenyl sulfonamide
With reference to the preparation method of embodiment 6, get faint yellow solid, yield:53.4%.
Embodiment 19
N-{4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-methoxyl biphenyl-2-alkylsulfonyl } propionic acid amide
With reference to embodiment 7 preparing methods, get white solid.Yield: 30.2%.mp?181-185℃。
IR(film，cm
-1)：3440，3113，3033，2353，2024，1706，1599，1477，1324，1146；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.972(3H，t，J＝7.5Hz，
CH 3CH
2)，1.969(2H，q，J＝7.5，7.5Hz，CH
3 CH 2)，3.862(s，3H，CH
3O)，5.425(2H，s)，6.730(1H，d，J＝2.1Hz)，7.023(1H，dd，J＝2.7，6.3Hz)，7.209～7.304(4H，m)，7.950(1H，s)，8.225(1H，s)，8.248(1H，d，J＝3.9Hz)，8.669(1H，s)；ESI-MS，m/z：399.1[(M-H)
-].
Embodiment 20
N-{4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-methoxyl biphenyl-2-alkylsulfonyl } valeramide
With reference to embodiment 8 preparing methods, get white solid.Yield: 45.1%.mp?94-98℃。
IR(film，cm
-1)：3417，3122，2959，2932，2871，2025，1715，1595，1130，1138；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.864(3H，t，J＝4.5Hz，
CH 3CH
2)，1.195～1.219(m，2H，CH
3 CH 2)，1.414～1.463(m，2H，CH
2 CH 2CH
2)，1.941(3H，t，J＝7.2Hz，CH
2 CH 2CO)，3.864(3H，s，CH
3O)，5.429(2H，s)，6.732(1H，d，J＝2.4Hz)，7.023(1H，dd，J＝2.4，6.3Hz)，7.238～7.311(m，3H)，7.956(1H，s)，7.227(1H，s)，7.256(1H，s)，8.758(1H，s)；ESI-MS，m/z：427[(M-H)
-].
Embodiment 21
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-methoxyl biphenyl-2-sulfoamido ethyl formate
With reference to embodiment 10 preparing methods, get white solid.Yield: 27.3%.mp?155-158℃。
1HNMR(CDCl
3，300MHz)：δ(ppm)1.160(3H，t，J＝6.9Hz，
CH 3CH
2)，3.869(s，3H，CH
3O)，4.068(2H，q，J＝7.2，7.2Hz，CH
3 CH 2CO)，5.433(2H，s)，6.744(1H，d，J＝1.5Hz)，6.003(1H，dd，J＝2.7，6.3Hz)，8.029(1H，s)，8.182(1H，d，J＝9.0Hz)，8.370(1H，s)；ESI-MS，m/z：415.1[(M-H)
-].
Embodiment 22
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-methoxyl biphenyl-2-sulfoamido t-butyl formate
With reference to embodiment 11 preparing methods, get white solid.Yield: 23.4%.mp?94-96℃。
IR(film，cm
-1)：3368，3129，2973，2024，1744，1592，1317，1156；
1HNMR(CDCl
3，300MHz)：δ(ppm)1.235(9H，s，t-Bu)，1.798(2H，s)，3.862(3H，s)，5.425(2H，s)，6.788(1H，s)，6.961(1H，d，J＝8.7Hz)，7.325(2H，d，J＝7.8Hz)，7.486(2H，d，J＝7.2Hz)，7.997(1H，s)，8.070(1H，d，J＝9.0Hz)，8.198(1H，s)；ESI-MS，m/z：443.2[(M-H)
-].
Embodiment 23
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-methoxyl biphenyl-2-sulfoamido butyl formate
With reference to embodiment 12 preparing methods, get white solid.Yield: 34.1%.mp?108-110℃。
IR(film，cm
-1)：3482，3120，2959，2933，2025，1751，1512，1331；
1HNMR(CDCl
3，300MHz)：δ(ppm)0.900(3H，t，J＝9.3Hz)，1.192～1.257(2H，m)，1.447～1.541(2H，m)，3.871(3H，s，CH
3O)，4.052(2H，t，J＝6.6Hz，CH
2 CH 2O)，5.408(2H，s)，6.760(2H，d，J＝2.7Hz)，7.0127(2H，dd，J＝2.4，6.3Hz)，7.248(1H，s)，7.268(2H，d，J＝3Hz)，7.348(2H，d，J＝8.1Hz)，7.507(1H，s)，7.981(1H，s)，8.161(1H，s)，8.203(2H，d，J＝9.0Hz)；ESI-MS，m/z：443.1[(M-H)
-].
Embodiment 24
4 '-[(1H-1,2,4-triazole-1-yl) methyl]-5-methoxyl biphenyl-2-sulfoamido benzyl formate
With reference to the preparation method of embodiment 13, get white solid.Yield 37.2%.mp?164-167℃。
IR(film，cm
-1)：3437，3032，2941，2024，1748，1593；
1HNMR(CDCl
3，300MHz)：δ(ppm)2.429(3H，s，CH
3O)，5.017(2H，s，CH
2O)，5.265(2H，s)，7.014(1H，s)，7.158～7.183(m，4H)，7.260～7.320(m，5H)，7.867(1H，s)，8.050(1H，s)，8.128(1H，d，J＝8.1Hz)；ESI-MS，m/z：477.2[(M-H)
-].
Embodiment 25
4 '-[(5-bromo-1H-1,2,4-triazole-1-yl) the methyl]-N-tertiary butyl-5-methyl-2-biphenyl sulphonyl ammonia
With 4 '-[(1H-1,2,4-triazole-1-yl) methyl]-(0.285g 0.742mmol) is dissolved in CHCl to 5-isobutyl--2-sulphonyl ammonia
3(10ml), add successively NBS (0.138g 0.779mmol) and AIBN (catalytic amount), stirs, and it is intact to raw material reaction that temperature rising reflux reacts, suction filtration, concentrating under reduced pressure, acetic acid ethyl dissolution, washing, anhydrous sodium sulfate drying spends the night, column chromatography (CH
2Cl
2: CH
3OH=60: 1) get 0.135g oily matter.Yield: 38.3%.
1HNMR(CDCl
3，300MHz)：6(ppm)0.971(9H，s，t-Bu)，2.419(3H，s，CH
3)，3.459(1H，s，NH)，5.420(2H，s，CH
2)，7.085(1H，s，H-4)，7.287(1H，d，J＝8.1Hz，H-6)，7.358(each?1H，d，J＝8.1Hz，CH
2-Ar)，7.516(each?1H，d，J＝8.1Hz，CH
2-Ar)，7.935(1H，s，3H)，8.035(1H，d，J＝8.1Hz，H-3).
Embodiment 26
4 '-[(5-bromo-1H-1,2,4-triazole-1-yl) methyl]-5-methyl diphenyl-2-sulphonyl ammonia butyl formate
With reference to embodiment 11 preparing methods, get faint yellow solid.Yield: 30.5%.mp?89-91℃。
1HNMR(CDCl
3，300MHz)：δ(ppm)0.914(3H，t，J＝7.8Hz，CH
3)，1.146(2H，m，CH
2)，1.408(2H，m，CH
2)，2.433(1H，s，CH
3)，4.012(2H，t，CH
2O)，5.383(2H，s)，7.013(1H，s)，7.094(1H，s)，7.264～7.364(m，5H)，7.911(1H，s)，8.138(1H，d，J＝8.2Hz).
ESI-MS，m/z：509[(M+H)
+]，M：[M+2]＝1∶1.
Embodiment 27
4 '-[(5-bromo-1H-1,2,4-triazole-1-yl) methyl]-5-isobutyl-biphenyl-2-sulphonyl ammonia butyl formate
With reference to embodiment 11 preparing methods, get faint yellow oily thing.Yield: 28.9%.
1HNMR(CDCl
3，300MHz)：δ(ppm)0.762(3H，t，J＝7.4Hz，CH
3)，0.848(6H，d，J＝6.5Hz)，1.335～1.350(2H，m，CH
3 CH 2)，1.809～2.022(1H，m)，2.486(2H，d，J＝7.1Hz，
CH 2CH)，3.956(2H，t，J＝6.7Hz，CH
2O)，5.342(s，2H)，6.997(1H，s)，7.134(1H，s)，7.234～7.279(5H，m)，7.916(1H，s)，8.131(1H，d，J＝3.9Hz)；
ESI-MS，m/z：547[(M-H)
-]，M：[M+2]＝1∶1.
Embodiment 28
4 '-[(5-bromo-1H-1,2,4-triazole-1-yl) methyl]-5-methoxyl biphenyl-2-sulphonyl ammonia butyl formate
With reference to embodiment 11 preparing methods, get faint yellow oily thing.Yield: 31.6%.mp?49-51℃。
1HNMR(CDCl
3，300MHz)：δ(ppm)1.485(2H，m)，1.751(2H，s)，3.866(3H，s，CH
3)，4.012(2H，t，J＝4.5Hz)，5.413(2H，s)，6.760(1H，s)，6.851(1H，s)，6.995(1H，d，J＝6.6Hz)，7.921(1H，s)，8.193(1H，d，J＝4.5Hz)；
ESI-MS，m/z：521[(M-H)
-]，M：[M+2]＝1∶1.
Embodiment 29
Get above-mentioned prescription, in flakes with the ordinary method preparation.
Claims (10)
1. the compound or pharmaceutically acceptable salt thereof of general formula (I):
R wherein
1Represent hydrogen, alkoxyl group, carboxyl, carbalkoxy, ester group;
R
2Represent hydrogen, C
1-C
6The alkyl of straight or branched, C
2-C
6The alkenyl of straight or branched, C
2-C
6The alkynyl of straight or branched, C
1-C
6The alkoxyl group of straight or branched, phenyl, fragrant heterocycle perhaps replace fragrant heterocycle, and said replacement heterocyclic base can be chosen wantonly from one or more C of being selected from
1-C
6Alkyl, C
1-C
6The substituted heterocyclic base of alkoxy or halogen, each substituting group is identical or different;
R
3Represent hydrogen, C
1-C
4Alkyl or halogen;
R
4Represent hydrogen, C
1-C
4Alkyl or alkoxyl group;
Ar represents phenyl ring or fragrant heterocycle, and said fragrant heterocycle refers to 1-2 the fragrant heterocycle of heteroatomic 5-6 unit, and said heteroatoms independently is selected from O, S or N separately;
2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R
1Be hydrogen, carbalkoxy or carbonyl.
3. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R
2Be hydrogen, C
1-C
6The alkyl of straight or branched, C
1-C
6The alkoxyl group of straight or branched.
4. the compound or pharmaceutically acceptable salt thereof of claim 3, wherein R
2Be C
1-C
4Straight chained alkyl or C
1-C
4The straight chain alkoxyl group.
5. the compound or pharmaceutically acceptable salt thereof of claim 4, wherein R
2Be methyl, isobutyl-or methoxyl group.
6. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R
3Be hydrogen or halogen.
7. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R
4Be hydrogen or alkyl.
8. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein Ar is phenyl ring, pyrrole ring or thiphene ring.
9. one kind is used to treat Mammals, is preferable over the pharmaceutical composition of treatment human diseases or illness, and it comprises treatment hypertension, congestive heart failure, myocardial hypertrophy, vasospasm and passes through exciting AT
2Acceptor is treated compound or its salt and pharmaceutically acceptable carrier of claim 1 of the significant quantity of other disease or illness.
10. the compound or its salt of claim 1 is treated hypertension, congestive heart failure, myocardial hypertrophy, vasospasm and is passed through exciting AT in preparation
2Acceptor is treated the application in the medicine of other illness.
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| US11407733B2 (en) | 2016-06-29 | 2022-08-09 | Bristol-Myers Squibb Company | Biarylmethyl heterocycles |
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